WO2004037159A2

WO2004037159A2 - Compounds, compositions and methods for modulating fat metabolism

Info

Publication number: WO2004037159A2
Application number: PCT/IL2003/000860
Authority: WO
Inventors: Georges Gaudriault; Ahmet Kilinc; Olivier Bousquet; Anne Goupil-Lamy; Itzik Harosh
Original assignee: Obetherapy Biotechnology
Priority date: 2002-10-23
Filing date: 2003-10-23
Publication date: 2004-05-06
Also published as: WO2004037159A3; AU2003274652A1; AU2003274652A8

Abstract

Methods, compositions and methods of identifying candidate compounds, for modulating fat metabolism and/or inhibiting Apobec-1 activity are provided.

Description

COMPOUNDS, COMPOSITIONS AND METHODS FOR MODULATING FAT

METABOLISM

FIELD AND BACKGROUND OF THE INVENTION The present invention relates to compounds, pharmaceutical compositions and methods which are useful for regulating an individual's fat metabolism and thus can be used in the treatment of diseases and disorders associated with fat metabolism and, more particularly, to compounds, pharmaceutical compositions and methods for treating disorders such as, but not limited to, overweight, obesity, atherosclerosis, hypertension, Type II or non-insulin dependent diabetes mellitus, pancreatitis, hypercholestrosaemia, hypertriglyceridaema and hyperlipidemia.

Obesity, defined as an excess of body fat relative to lean body mass, is becoming a major public health problem, particularly in industrialized countries. In the U.S. alone, according to the third National Health and Nutrition Examination Survey (1995 NHANES III), obesity and overweight affect more than one-half of the U.S. adult population. Increased numbers of obese individuals have also been recently reported all over Europe. By any criteria, obesity represents a chronic disease, which is associated with a wide range of psychological and medical co- morbidities, such as, for example, atherosclerosis, hypertension, Type II or non- insulin dependent diabetes mellitus, pancreatitis, hypercholestrosaemia, hypertriglyceridaema and hyperlipidemia.

Obesity related genes have been described in the art as targets for the treatment of obesity many years ago. These genes include, for example, the obese gene (ob), which encodes for the circulating hormone leptin, and its receptor, the diabetes gene (db) (Tartaglia et al. Cell 83(7): 1263-71; Zhang et al. Nature 372(6505): 425-32.). However, it was found that obese patients have high levels of leptin and are therefore leptin-resistant, a phenomenon that resembles insulin- resistance in diabetic patients (Considine et al, N Engl J Med 334(5): 292-5; Maffei et al., Diabetes 45(5): 679-82). Additional examples of obesity related genes include agouti (ag), tubby (tub), fat (fat), mahogany and neuropeptide Y (NPY) (Flier and Maratos-Flier, Cell 92(4): 437-40; Spiegelman and Flier, Cell 87(3): 377-89; Nagle et al., Nature 398: 148-152; Gunn et al., Nature, 398: 152-156), all of which are associated with the central nervous system (CNS) and therefore have divergent physiological targets in addition to energy balance and obesity. In addition to these genes, it has recently been suggested that the uncoupling mitochondrial proteins

(UCP1) and (UCP2), by blocking the formation of ATP and thus increasing glucose burning, may also serve as targets for obesity treatment (Fleurye et al., Nat Genet

15(3): 269-72; Boss et al., FEBS Lett 408: 39-42; Bouchard et al., Hum Molec Genet 11: 1887-1889). However, all these proposed targets, as well as other obesity related genes, are highly limited by their non-specificity and redundancy, which lead to substantial side effects associated with their manipulation (Nagle et al., Nature 398: 148-152; Gunn et al, Nature, 398: 152-156; Lu et al., Nature 371: 799-802; Cool et al., Cell 88: 73-83). Furthermore, a lean phenotype has never been observed as a result of knocking out these genes. Moreover, based on the "thrifty gene" theory, which is described in detail by Neel (Am. J. Hum. Genet., 1962, 14, 353-362) and Coleman (Science, 1979, 263, 663-665), it was proposed that in most cases obesity involves many genes that interact and create a complex network of redundant biochemical pathways that stimulate appetite or satiety. The inhibition or activation of a single pathway is therefore compensated by alternative inherited pathways in order to save energy.

At present, only a limited number of drugs for treating obesity are commercially available. Unfortunately, while some of these drugs may bring short- term relief to the patient, a long-term successful treatment has not been achieved yet. Exemplary methods of treating obesity are also disclosed in U.S. Pat. Nos. 3,867,539; 4,446,138; 4,588,724; 4,745,122; 5,019,594; 5,300,298; 5,403,851; 5,567,714; 5,573,774; 5,578,613 and 5,900,411.

One of the presently available drugs for treating obesity, developed by Hoffman-LaRoche, is an inhibitor of pancreatic lipase (PL). Pancreatic lipase is responsible for the degradation of triglycerides to monoglycerides. However, as its inhibition is associated with severe diarrhea and, furthermore, results in absorption inhibition of only one specific fraction of fatty acid, treatment with PL inhibitors is highly disadvantageous and may even expose the treated subject to life-threatening risks. Recently, it has been suggested that fat absorption may be reduced by inhibiting the activity of the microsomal triglyceride-transfer protein (MTP), which is responsible for the formation and secretion of VLDL and chylomicrons. Sharp et al. (Nature 365:65-69, 1994) and Wetterau et al (Science 282:751-754, 1994) demonstrated that the MTP gene is involved in abetalipoproteinemia disease. U.S.

Pat. Nos. 6,066,650, 6,121,283 and 6,369,075 describe compositions that include

MTP inhibitors, which are aimed at treating various conditions associated with excessive fat absorption. However, treatments with MTP inhibitors suffer major disadvantages, which are attributed to the MTP expression in both the intestine and the liver. It was found that inhibition of the MTP activity in the liver resulted in severe side effects, an example of which is a development of a fatty liver [Kane and

Havel (1989). Disorders of the biogenesis and secretion of lipoproteins containing the apolipoprotein B. pp. 1139-1164 in: "The metabolic basis of inherited disease" (Scrivers et al, eds). McGraw-Hill, New York]. In fact, the company which developed MTP inhibitors as targets for treating obesity, Brystol Myers Squibb, has recently decided to abandon this target, due to the fatty liver side effect arising from the its mechanism of action.

The presently known targets for the treatment of obesity and related disorders can be divided into four main classes: (i) appetite blockers, which include for example the NPY neuropeptide; (ii) satiety stimulators, which include, for example, the ob, db and agouti genes; (iii) energy or fatty acid burning agents, which include the UCPs; and (iv) fat absorption inhibitors such as the PL and MTP, described above.

As is discussed hereinabove, these targets are highly limited by their redundancy, multiple targeting and/or lack of tissue specificity.

There is thus a widely recognized need for, and it would be highly advantageous to have, compounds compositions ^"and methods for treating obesity and related diseases and disorders devoid of the above limitations.

In a search for a selective fat absorption inhibition, which would be devoid of the above limitations, it was suggested that Anderson disease related genes, which modulate or partially inhibit the formation and secretion of chylomicrons only in the intestine, may serve as selective and efficient targets for treating obesity, as is detailed in FR 97 16655 and FR 97 04388, which are incorporated by reference as if fully set forth herein. The Anderson disease is a rare monogenic disease characterized by fat malabsorption and, more specifically, by the absence of chylomicrons. The chylomicrons are vesicles which transport dietary fat, which contain apolipoprotein B48 (apoB48) and are normally exclusively produced by the intestine. The apoB48 protein is produced as a result of a post-transcriptional editing by the apoB mRNA editing protein named Apobec-1. The Apobec-1 editing protein deaminates cytidine to uridine, at position 6666 (GenBank Accession No. NP_001635) of the apoB mRNA, and produces a UAA in-frame stop codon (Chan, Biochimie, 77:75-78; Chan and Seeburg Scientific American Science and Medicine 2:68-77). It was thus postulated that by selectively inhibiting Apobec-1 activity, the formation of fat- transporting chylomicrons and, as a consequence, the absoφtion of fatty acids, would be reduced. Since Apobec-1 activity is limited to the intestine, inhibition of this protein would result in substantially less harmful, if any, side effects. It was therefore postulated that effective inhibition of Apobec-1 would result in (i) selective inhibition of the formation of chylomicrons in the intestine, thereby minimizing side effects; (ii) enabling patients to continue eating ad libitum; and (iii) enabling oral administration of the inhibitor.

U.S. Pat. No. 6,210,888, which is incorporated herein by reference, teaches molecular-based methods for identifying molecules which are capable of inhibiting deaminating ezymes, such as Apobec-1. Briefly, the method is based on the ability to detect the presence or absence of a deaminated cytosine in a defined nucleic acid sequence using labeled primers which hybridize 3' of the deaminated site. The primer hybridizes with the nucleic acid template in the presence of an appropriate polymerase and modified adenine. If the site to be assayed is deaminated, one to three nucleotides are added to each primer hybridized to the nucleic acid template. Conversely, to detect the absence of deamination of a site, modified guanine is used. Following extension, the primers are denatured and placed in the presence of an exposure system, to quantify the incorporation of the modified nucleotides. Using this methodology it is possible to identify molecules which affect an enzyme deaminase activity. U.S. Pat. No. 6,210,888 therefore teaches methods of screening for deaminase inhibiting molecules, which require the performance of a biological assay for each of the screened molecules, and as such are time consuming, expensive and require high technical skills. There is thus a widely recognized need for, and it would be highly advantageous to have a more efficient method for identifying compounds for treating obesity and related diseases and disorders devoid of the above limitations. SUMMARY OF THE INVENTION

According to one aspect of the present invention there is provided a method of modulating fat metabolism in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having a general Formulae I, II, III, IN or N:

Formula I Formula II

Formula III

Formula IN

R¹⁴-M-R¹⁵-L-R¹⁶-Mι-R¹⁸-Lι-R¹⁹

Formula N

or a pharmaceutically acceptable salt thereof, wherein,

A and B are each independently Ν or CRa;

W is -CR²⁰R²¹-CR²²R²³-,

-

R )3^J2C, =N-, -N=CR >3^J3S -N=N-, -NR ,3^J4⁴-NR >3^J5^D-, R*TST-CR ,3^J7^/_= or =R ,3^j8⁸ _/C-NR >3^j9^y, or absent; Q -CR⁴⁰R⁴¹-, -NR⁴²-, -CR⁴³R⁴⁴-CR⁴⁵R⁴⁶-, -CR⁴⁷=CR⁴⁸-, R⁴⁹R⁵⁰C-NR⁵¹-, -

R⁵²N-CR⁵³R⁵⁴, -R⁵⁵C=N-, -N=CR⁵⁶-, -N=N-, -NR⁵⁷-NR⁵⁸-, R⁵⁹N-CR⁶⁰= or =R⁶¹C-

NR⁶², or absent;

X, Y and Z are each independently O, NRb, S, -CR⁶³R⁶⁴- or -R⁶⁵R⁶⁶C- CR⁶⁷R⁶⁸;

V is O, S, Pd, -NR⁶⁹, -CR⁷⁰R⁷¹-, -R⁷²R⁷³C-CR⁷⁴R⁷⁵-, -R⁷⁶R⁷⁷C-CR⁷⁸R⁷⁹- CR⁸⁰R⁸¹-, -R⁸²R⁸³C-CR⁸⁴R⁸⁵-CR⁸⁶R⁸⁷-CR⁸⁸R⁸⁹-, -R⁹⁰C=CR⁹¹-, -R⁹²R⁹³C-NR⁹⁴- CR⁹⁵R⁹⁶-, -R⁹⁷R⁹⁸C-NR⁹⁹R¹⁰⁰, -R¹⁰¹R¹⁰²C-NR¹⁰³R¹⁰⁴-CR¹⁰⁵R¹⁰⁶-NR¹⁰⁷R¹⁰⁸- or -O-

_CR109_R110. U is an alkyl having 1-20 carbon atoms, an alkyl having 1-20 carbon atoms interrupted by at least one heteroatom selected from the group consisting of O, N and S, or absent;

D, E and F are each independently -CR^mR¹¹²-, -NR¹¹³-, O, S, -CR¹¹⁴R¹¹⁵- CR¹¹⁶R¹¹⁷-, -CR¹¹⁸=CR¹¹⁹-, R¹²⁰R¹²¹C-NR¹²²-, -R¹²³N-CR¹²⁴R¹²⁵-, -R¹²⁶C=N-, - N=CR¹²⁷-, -N=N-, -NR¹²⁸-NR¹²⁹-, R¹³⁰N-CR¹³¹= or =R¹³²C-NR¹³³, or absent;

G, I and J are each independently -CR¹³⁴R¹³⁵-, -NR¹³⁶-, -CR¹³⁷R¹³⁸-CR^I39R¹⁴⁰-, -CR¹⁴¹=CR¹⁴²-, -R¹⁴³R¹⁴⁴C-NR¹⁴⁵-, -R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-, -R¹⁴ C=N-, -N=CR¹⁵⁰-, -N=N- , -NR¹⁵¹-NR¹⁵²-, R¹⁵³N-CR¹⁵⁴= or =R¹⁵⁵C-NR¹⁵⁶, or absent; Li and 1^ are each independently C, CRc or N; T is-CR¹⁵⁷R¹⁵⁸R¹⁵⁹,-CR¹⁶⁰R¹⁶¹-CR¹⁶²R¹⁶³R¹⁶⁴ or-R¹⁶⁵;

M is C=O, S=O, P=O, C=S, C=N-R¹⁶⁶, S=N-R¹⁶⁷, N=N-R¹⁶⁸ or C=C-R¹⁶⁹; Mi, L and Lj are each independently C=O, S=O, P=O, C=S, C=N-R¹⁷⁰, S=N- R¹⁷¹, N=N-R¹⁷² or C=C-R¹⁷³ or absent; and

Each of Ra, Rb, Re and R^R¹⁷³ is independently is independently selected from the group consisting of hydrogen, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, trihalomethanesulfonamido, guanyl, guanidino, carbohydrate, and amino, or, alternatively, at least two of R², R³ and R²⁰-R⁶² form at least one four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula I, at least two of R⁶³-R¹¹⁰ form at least one three-, four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula II, at least two of R 1 11 -R 133 form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring and/or at least two of R¹³⁴-R¹⁵⁶ form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula III, and at least two of R³-R¹³ and/or of R¹⁵⁷-R¹⁶⁴ form a three-, four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula IN.

According to another aspect of the present invention there is provided a method of modulating fat metabolism in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of any of the compounds listed in Tables 1-5.

According to yet another aspect of the present invention there is provided a method of modulating fat metabolism in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound capable of inhibiting Apobec-1 activity.

According to further features in preferred embodiments of the invention described below, the modulating of the fat metabolism is for a treatment of a condition or disorder selected from the group consisting of overweight, obesity, type II diabetes, hypercholesterolemia, atherosclerosis, hypertension, pancreatitis, hypertriglyceridaema and hyperlipidemia.

According to still another aspect of the present invention there is provided a method of inhibiting Apobec-1 activity, the method comprising exposing an Apobec-1 to an inhibitory amount of a compound having a general Formulae I, II, III, IN or N:

Formula I Formula II

Formula III

Formula IN

R¹⁴-M-R^M-L-R¹⁶-Mι4l^u-Lι-R¹⁹

Formula V

or a pharmaceutically acceptable salt thereof, wherein,

A and B are each independently Ν or CRa;

W is -CR²⁰R²¹-CR²²R²³-, -CR²⁴=CR²⁵-, -R²⁶R²⁷C-ΝR²⁸-, -R²⁹N-CR³⁰R³¹-, - R³²C-N-, -N=CR³³-, -N=N-, -NR³⁴-NR³⁵-, R³⁶N-CR³⁷= or =R³⁸C-NR³⁹, or absent; Q -CR⁴⁰R⁴¹-, -NR⁴²-, -CR⁴³R⁴⁴-CR⁴⁵R⁴⁶-, -CR⁴⁷=CR⁴⁸-, R⁴⁹R⁵⁰C-NR⁵¹-, -

R⁵²N-CR⁵³R⁵⁴, -R⁵⁵C=N-, -N=CR⁵⁶-, -N=N-, -NR⁵⁷-NR⁵⁸-, R⁵⁹N-CR⁶⁰= or =R⁶¹C- NR⁶², or absent;

X, Y and Z are each independently O, NRb, S, -CR⁶³R⁶⁴- or -R⁶⁵R⁶⁶C-

_CR67_R68. V is O, S, Pd, -NR⁶⁹, -CR⁷⁰R⁷¹-, -R⁷²R⁷³C-CR⁷⁴R⁷⁵-, -R⁷⁶R⁷⁷C-CR⁷⁸R⁷⁹-

CR⁸⁰R⁸¹-, -R⁸²R⁸³C-CR⁸⁴R⁸⁵-CR⁸⁶R⁸⁷-CR⁸⁸R⁸⁹-, -R⁹⁰C=CR⁹¹-, -R⁹²R⁹³C-NR⁹⁴- CR⁹⁵R⁹⁶-, -R⁹⁷R⁹⁸C-NR⁹⁹R¹⁰⁰, -R¹⁰¹R¹⁰²C-NR¹⁰³R¹⁰⁴-CR¹⁰⁵R¹⁰⁶-NR¹⁰⁷R¹⁰⁸- or -O-

_CR109_R110.

U is an alkyl having 1-20 carbon atoms, an alkyl having 1-20 carbon atoms interrupted by at least one heteroatom selected from the group consisting of O, N and S, or absent; D, E and F are each independently -CR^mR¹¹²-, -NR¹¹³-, O, S, -CR¹¹⁴R¹¹⁵-

CR¹¹⁶R¹¹⁷-, -CR¹¹⁸-CR¹¹⁹-, R¹²⁰R¹²¹C-NR¹²²-, -R¹²³N-CR¹²⁴R¹²⁵-, -R¹²⁶C=N-, -

N=CR¹²⁷-, -N=N-, NR¹²⁸-NR¹²⁹-, R¹³⁰N-CR¹³¹= or =R¹³²C-NR¹³³, or absent;

G, I and J are each independently-CR¹³⁴R¹³⁵-, -NR¹³⁶-, -CR¹³⁷R¹³⁸-CR¹³⁹R¹⁴⁰-, -CR¹⁴¹=CR¹⁴²-, -R¹⁴³R¹⁴⁴C-NR¹⁴⁵-, -R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-, -R^l49C=N-, -N=CR¹⁵⁰-, -N=N-

, -NR¹⁵¹-NR¹⁵²-, R¹⁵³N-CR¹⁵⁴= or =R¹⁵⁵C-NR¹⁵⁶, or absent;

Li and 1^ are each independently C, CRc or N;

T is^CR¹⁵⁷R¹⁵⁸R¹⁵⁹,-CR¹⁶⁰R¹⁶¹-CR¹⁶²R¹⁶³R¹⁶⁴or-R¹⁶⁵;

M is C=O, S=O, P=O, OS, C=N-R¹⁶⁶, S=N-R¹⁶⁷, N=N-R¹⁶⁸ or C=C-R¹⁶⁹; Mi, L and Li are each independently C=O, S=O, P=O, C=S, C=N-R¹⁷⁰, S=N-

R¹⁷¹, N=N-R¹⁷² or C=C-R¹⁷³ or absent; and

Each of Ra, Rb, Re and R^R¹⁷³ is independently is independently selected from the group consisting of hydrogen, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, trihalomethanesulfonamido, guanyl, guanidino, carbohydrate, and amino, or, alternatively, at least two of R², R³ and R²⁰-R⁶² form at least one four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula I, at least two of R -R ¹ form at least one three-, four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula II, at least two of R^{U 1}-R¹³³ form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring and/or at least two of R¹³⁴-R¹⁵⁶ form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula III, and at least two of R³-R¹³ and/or of R¹⁵⁷-R¹⁶⁴ form a three-, four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula IV. According to an additional aspect of the present invention there is provided a method of inhibiting Apobec-1 activity, the method comprising exposing an Apobec- 1 to an inhibitory amount of any of the compounds listed in Tales 1-5. According to yet an additional aspect of the present invention there is provided a pharmaceutical composition for the treatment or prevention of a condition or disorder in which modulating fat metabolism is beneficial, comprising, as an active ingredient, a compound capable of inhibiting an Apobec-1 activity, and a pharmaceutically acceptable carrier.

According to still an additional aspect of the present invention there is provided a pharmaceutical composition for the treatment or prevention of a condition or disorder in which modulating fat metabolism is beneficial, comprising, as an active ingredient, any of the compound listed in Tabled 1-5, and a pharmaceutically acceptable carrier.

According to a further aspect of the present invention there is provided a pharmaceutical composition for the treatment or prevention of a condition or disorder in which modulating fat metabolism is beneficial, comprising, a pharmaceutically acceptable carrier, and, as an active ingredient, a compound having a general Formulae I, II, III, IV or V:

Formula I ^■ Formula II

Formula III

Formula IV

Formula V

or a pharmaceutically acceptable salt thereof, wherein,

A and B are each independently N or CRa;

W is -CR²⁰R²¹-CR²²R²³-, -CR²⁴=CR²⁵-, -R²⁶R²⁷C-NR²⁸-, -R²⁹N-CR³⁰R³¹-, - R³²C=N-, -N=CR³³-, -N=N-, -NR³⁴-NR³⁵-, R³⁶N-CR³⁷= or =R³⁸C-NR³⁹, or absent;

Q -CR⁴⁰R⁴¹-, -NR⁴²-, -CR⁴³R⁴⁴-CR⁴⁵R⁴⁶-, -CR⁴⁷=CR⁴⁸-, R⁴⁹R⁵⁰C-NR⁵¹-, - R⁵²N-CR⁵³R⁵⁴, -R⁵⁵C=N-, -N=CR⁵⁶-, -N=N-, -NR⁵⁷-NR⁵⁸-, R⁵⁹N-CR⁶⁰= or =R⁶¹C- NR⁶², or absent;

V is O, S, Pd, -NR⁶⁹, -CR⁷⁰R⁷¹-, -R⁷²R⁷³C-CR⁷⁴R⁷⁵-, -R⁷⁶R⁷⁷C-CR⁷⁸R⁷⁹- CR⁸⁰R⁸¹-, -R⁸²R⁸³C-CR⁸⁴R⁸⁵-CR⁸⁶R⁸⁷-CR⁸⁸R⁸⁹-, -R⁹⁰C=CR⁹¹-, -R⁹²R ³C-NR⁹⁴-

CR⁹⁵R⁹⁶-, -R⁹⁷R⁹⁸C-NR⁹⁹R¹⁰⁰, -R¹⁰¹R¹⁰²C-NR¹⁰³R¹⁰⁴-CR¹⁰⁵R¹⁰⁶-NR¹⁰⁷R¹⁰⁸- or -O-

_CR109_R110.

U is an alkyl having 1-20 carbon atoms, an alkyl having 1-20 carbon atoms interrupted by at least one heteroatom selected from the group consisting of O, N and S, or absent;

D, E and F are each independently -CR^mR¹¹²-, -NR¹¹³-, O, S, -CR¹¹⁴R¹¹⁵- CR¹¹⁶R¹¹⁷-, -CR¹¹⁸=CR¹¹⁹-, R¹²⁰R¹²¹C-NR¹²²- -R¹²³N-CR¹² R¹²⁵-, -R¹²⁶C=N-, - N=CR¹²⁷-, -N=N-, -NR¹²⁸-NR¹²⁹-, R¹³⁰N-CR¹³¹= or =R¹³²C-NR¹³³, or absent;

G, I and J are each independently -CR¹³⁴R¹³⁵-, -NR¹³⁶-, -CR¹³⁷R¹³⁸-CR¹³⁹R¹⁴⁰-, -CR¹⁴¹=CR¹⁴²-, -R¹⁴³R¹⁴⁴C-NR¹⁴⁵-, -R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-, -R¹⁴⁹C=N-, -N=CR¹⁵⁰-, -N=N- , -NR¹⁵¹-NR¹⁵²-, R¹⁵³N-CR¹⁵⁴= or =R¹⁵⁵C-NR¹⁵⁶, or absent;

Li and 1^ are each independently C, CRc or N;

T is-CR¹⁵⁷R¹⁵⁸R¹⁵⁹,-CR¹⁶⁰R¹⁶¹-CR¹⁶²R¹⁶³R¹⁶⁴ or- ¹⁶⁵;

M is C=O, S=O, P=O, C=S, C=N-R¹⁶⁶, S=N-R¹⁶⁷, N=N-R¹⁶⁸ or C=C-R¹⁶⁹; Mi, L and Li are each independently C=O, S=O, P=O, C=S, C=N-R¹⁷⁰, S=N-

R¹⁷¹, N=N-R¹⁷² or C-C-R¹⁷³ or absent; and

Each of Ra, Rb, Re and R^!-R¹⁷³ is independently is independently selected from the group consisting of hydrogen, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, trihalomethanesulfonamido, guanyl, guanidino, carbohydrate, and amino, or, alternatively, at least two of R², R³ and R²⁰-R⁶² form at least one four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula I, at least two of R⁶³-R¹¹⁰ form at least one three-, four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula II, at least two of R -R form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring and/or at least two of R¹³⁴-R¹⁵⁶ form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula III, and at least two of R³-R¹³ and/or of R¹⁵⁷-R¹⁶⁴ form a three-, four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula TV.

According to yet a further aspect of the present invention there is provided a method of identifying a candidate compound for modulating fat metabolism by inhibiting Apobec-1 activity, the method comprising: obtaining a set of structural coordinates defining the three-dimensional structure of at least the active site cavity of Apobec-1; and computationally identifying a compound which is capable of specifically binding to the three-dimensional structure of the active site cavity, thereby identifying the candidate compound for modulating fat metabolism by inhibiting Apobec-1 activity.

According to still a further aspect of the present invention there is provided a method of identifying a candidate compound for modulating fat metabolism by inhibiting Apobec-1 activity, the method comprising: obtaining a set of structural coordinates defining the three-dimensional structure of at least the active site cavity of Apobec-1; and computationally identifying a compound which is capable of specifically binding to the three-dimensional structure of the active site cavity, thereby identifying the candidate compound for modulating fat metabolism by inhibiting Apobec-1 activity. According to still further features in the described preferred embodiments identifying is effected by: determining a position and orientation of at least one pharmacophore interacting moiety in the active site cavity; and identifying a compound that both spatially and chemically fits to the three-dimensional structure of the active site cavity.

According to still further features in the described preferred embodiments the at least one pharmacophore interacting moiety comprises a plurality of pharmacophore interacting moieties, whereby the identifying the compound that chemically binds to the three-dimensional structure of the active site cavity is based on at least one of a plurality of combinations of the plurality of pharmacophore interacting moieties.

According to still further features in the described preferred embodiments the determining a position and orientation of the at least one pharmacophore interacting moiety is by computational means. According to still further features in the described preferred embodiments the identifying is by computational means.

According to still further features in the described preferred embodiments the obtaining the set of structural coordinates is by computational means.

According to still a further aspect of the present invention there is provided a computer readable medium comprising a data storing device storing therein in a retrievable or executable format a computational representation of a set of structural coordinates defining a three-dimensional structure of at least an active site cavity of Apobec-1 and of at least one pharmacophore interacting moiety in the active site cavity of Apobec-1. According to still a further aspect of the present invention there is provided a computer readable medium comprising a data storing device storing, in a retrievable or executable format, data including a set of structure coordinates defining at least a portion of a three-dimensional structure of Apobec-1.

According to still further features in the described preferred embodiments the data including the set of structure coordinates defining at least the portion of the three- dimensional structure of Apobec-1 is derived from the set of coordinates presented in the Table of Figures 1-96. According to still a further aspect of the present invention there is provided a computer readable medium comprising a data storing device storing in a retrievable or executable format, data including a set of structural coordinates defining at least a portion of a three-dimensional structure of Apobec-1 complexed with an Apobec-1 inhibitor.

According to still a further aspect of the present invention there is provided a method of identifying a candidate compound for inhibiting Apobec-1 activity, the method comprising: obtaining a set of structural coordinates defining a three- dimensional atomic structure of at least the active site cavity of Apobec-1; and computationally screening a plurality of compounds for a compound capable of specifically binding the active site cavity, thereby identifying the candidate compound for inhibiting Apobec-1 activity.

According to still a further aspect of the present invention there is provided a computing platform for generating a three-dimensional model of at least the active site cavity of Apobec-1, the computing platform comprising: a data-storage device storing data comprising a set of structural coordinates defining at least the active site cavity of Apobec-1; and a processing unit being for generating the three-dimensional model from the data stored in the data-storage device.

According to still a further aspect of the present invention there is provided a computing platform for generating a three-dimensional model of at least a portion of Apobec-1 complexed with an Apobec-1 inhibitor, the computing platform comprising: a data-storage device storing data comprising a set of structural coordinates defining at least a portion of a three-dimensional structure of at least the active site of Apobec-1 complexed with the Apobec-1 inhibitor; and a processing unit being for generating the three-dimensional model from the data stored in the datastorage device.

According to still a further aspect of the present invention there is provided a method of identifying a candidate compound for modulating fat metabolism by inhibiting Apobec-1 activity, the method comprising: identifying a compound that spatially and chemically binds to a three-dimensional structure of the active site cavity of Apobec-1; and biologically assaying the compound for its activity in inhibiting Apobec-1 and/or in modulating fat metabolism. According to still further features in the described preferred embodiments the biologically assaying the compound in effected by an assay selected from the group consisting of: determining fat levels in a biological sample; determining apoB expression; determining apoB secretion; and determining cytidine deaminase activity.

According to still further features in the described preferred embodiments the compound has a general Formulae I, II, III, IN or V:

Formula I Formula II

Formula III

Formula IV

R¹⁴-M-R¹⁵-L R¹⁶-Mι-R¹⁸-Lι-R¹⁹

Formula V

or a pharmaceutically acceptable salt thereof, wherein,

A and B are each independently Ν or CRa;

W is -CR²⁰R²¹-CR²²R²³-, -CR²⁴=CR²⁵-, -R²⁶R²⁷C-ΝR²⁸-, -R²⁹N-CR³⁰R³¹-, R³²C=N-, -N=CR³³-, -N=N-, -NR³⁴-NR³⁵-, R³⁶N-CR³⁷= or =R³⁸C-NR³⁹, or absent; Q -CR^R⁴¹-, -NR⁴²-, -CR⁴³R⁴⁴-CR⁴⁵R⁴⁶-, -CR⁴⁷=CR⁴⁸-, R⁴⁹R^S0C-NR⁵¹-, -

NR⁶², or absent;

V is O, S, Pd, -NR⁶⁹, -CR⁷⁰R⁷¹-, -R⁷²R⁷³C-CR⁷⁴R⁷⁵-, -R⁷⁶R⁷⁷C-CR⁷⁸R⁷⁹- CR⁸⁰R⁸¹-, -R⁸²R⁸³C-CR⁸⁴R⁸⁵-CR⁸⁶R⁸⁷-CR⁸⁸R⁸⁹-, -R⁹⁰OCR⁹¹-, -R⁹²R⁹³C-NR⁹⁴- CR⁹⁵R⁹⁶-, -R⁹⁷R⁹⁸C-NR⁹⁹R¹⁰⁰, -R¹⁰¹R¹⁰²C-NR¹⁰³R¹⁰⁴-CR¹⁰⁵R¹⁰⁶-NR¹⁰⁷R¹⁰⁸- or -O-

_CR109_R11Q. U is an alkyl having 1-20 carbon atoms, an alkyl having 1-20 carbon atoms interrupted by at least one heteroatom selected from the group consisting of O, N and S, or absent;

D, E and F are each independently -CR^mR¹¹²-, -NR¹¹³-, O, S, -CR¹¹⁴R¹¹⁵- CR¹¹⁶R¹¹⁷-, -CR¹¹⁸= R¹¹⁹-, R¹²⁰R^I21C-NR¹²²-, -R¹²³N-CR¹²⁴R¹²⁵-, -R¹²⁶ON-, - N= R¹²⁷-, -N=N-, -NR¹²⁸-NR¹²⁹-, R¹³⁰N-CR¹³¹= or =R¹³²C-NR¹³³, or absent;

G, I and J are each independently -CR¹³⁴R¹³⁵-, -NR¹³⁶-, -CR¹³⁷R¹³⁸-CR¹³⁹R¹⁴⁰-,

, -NR¹⁵¹-NR¹⁵²-, R¹⁵³N-CR¹⁵⁴= or =R¹⁵⁵C-NR¹⁵⁶, or absent; Li and L₂ are each independently C, CRc or N; T is-OR¹⁵⁷R¹⁵⁸R¹⁵⁹,-CR¹⁶⁰R¹⁶¹-CR¹⁶²R¹⁶³R¹⁶⁴ or^.¹⁶⁵;

M is OO, S=O, P=O, OS, ON-R¹⁶⁶, S=N-R¹⁶⁷, N=N-R¹⁶⁸ or OC-R¹⁶⁹; Mi, L and Li are each independently OO, S=O, P=O, OS, ON-R¹⁷⁰, S=N- R¹⁷¹, N=N-R¹⁷² or OC-R¹⁷³ or absent; and

Each of Ra, Rb, Re and R^!-R¹⁷³ is independently is independently selected from the group consisting of hydrogen, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, trihalomethanesulfonamido, guanyl, guanidino, carbohydrate, and amino, or, alternatively, at least two of R , R and R -R form at least one four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula I, at least two of R⁶³-R¹¹⁰ form at least one three-, four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula II, at least two of R -R form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring and/or at least two of R¹³⁴-R¹⁵⁶ form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula III, and at least two of R³-R¹³ and/or of R¹⁵⁷-R¹⁶⁴ form a three-, four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula IV.

According to still further features in the described preferred embodiments the compound has a general Formula I.

According to still further features in the described preferred embodiments, A and B are each CRa; W is~N=CR³³-; and Q is -CR⁴⁷=CR⁴⁸-. According to still further features in the described preferred embodiments,

A is N; B is CRa;

W is-N=CR³³-; and Q is -CR⁴⁷=CR⁴⁸-. According to still further features in the described preferred embodiments,

A is CRa; B is N;

W is-R³²ON-; and Q is-R⁵⁵ N. According to still further features in the described preferred embodiments,

A and B are each CRa; W is-R³² N-; and Q is-R⁴⁹R⁵⁰C-NR⁵¹-.

According to still further features in the described preferred embodiments, A and B are each CRa;

W is-R²⁶R²⁷C-NR²⁸-; and

Q is-R⁴⁹R⁵⁰C-NR⁵¹-.

W is-CR²⁴=CR²⁵; and

Q is-CR⁴⁷=CR⁴⁸.

W is =N=CR³³-; and

Q is NR⁴².

According to still further features in the described preferred embodiments,

A and B are each CRa; W is-R³²ON-; and

Q is NR⁴².

According to still further features in the described preferred embodiments,

A and B are each CRa;

W is-R²⁶R²⁷C-NR²⁸-; and Q is NR⁴².

According to still further features in the described preferred embodiments,

A is N;

B is CRa;

W is^CR²⁰R²¹-CR²²R²³-; and Q is NR⁴².

According to still further features in the described preferred embodiments,

A and B are each N;

W is-CR²⁰R²¹-CR²²R²³-; and

Q is NR⁴². According to still further features in the described preferred embodiments,

A is N;

B is CRa;

W is R²⁹N-CR³⁰R³¹; and

Q is-CR⁴⁰R⁴¹. According to still further features in the described preferred embodiments,

A and B are each N;

W is -R²⁹N-CR³⁰R³¹; and

A and B are each CRa;

W is -R²⁶R²⁷C-NR²⁸-; and

A is N;

B is CRa;

W is-CR²⁰R²¹-CR²²R²³-; and

A and B are each N;

W is -R²⁹N-CR³⁰R³¹; and

Q is^CR⁴³R⁴⁴-CR⁴⁵R⁴⁶.

According to still further features in the described preferred embodiments the compound has the general Formula II.

According to still further features in the described preferred embodiments,

V is-R⁷²R⁷³C-CR⁷⁴R⁷⁵-; and U is absent.

According to still further features in the described preferred embodiments, X and Z are each -CR⁶³R⁶⁴-; and

Y is O.

According to still further features in the described preferred embodiments each of R , R , R , R , R and R is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl. According to still further features in the described preferred embodiments,

X and Z are each oxygen; and

Y is -CR⁶³R⁶⁴-.

According to still further features in the described preferred embodiments each of R , R , R , R , R and R is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

According to still further features in the described preferred embodiments, V is-R⁸²R⁸³C-CR⁸⁴R⁸⁵-CR⁸⁶R⁸⁷-CR⁸⁸R⁸⁹-; and U is absent. According to still further features in the described preferred embodiments,

X and Z are each -CR⁶³R⁶⁴-; and

Y is O.

According to still further features in the described preferred embodiments each of R⁶³, R⁶⁴, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸ and R⁸⁹ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

According to still further features in the described preferred embodiments,

X and Z are each oxygen; and

Y is -CR⁶³R⁶⁴-. According to still further features in the described preferred embodiments each of R⁶³, R⁶⁴, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸ and R⁸⁹ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

According to still further features in the described preferred embodiments the compound has the general Formula III. According to still further features in the described preferred embodiments,

Li and L₂ are each C;

D is N;

E is-CR^mR¹¹²-;

F is-NR¹¹³-; J and G are each-N=CR¹⁵⁰-; and

I is absent.

According to still further features in the described preferred embodiments,

Li and L₂ are each C;

D is -N=CR¹²⁷-; E is absent;

F is-NR¹¹³-;

J and G are each-N=CR¹⁵⁰-; and

I is absent.

According to still further features in the described preferred embodiments, Li and L₂ are each C;

D is-NR¹¹³-;

E is absent;

F is-R¹²⁶ON-; J and G are each-N=CR¹⁵⁰-; and

I is absent.

According to still further features in the described preferred embodiments,

D is-NR¹¹³-; E is absent;

F is-CR¹¹⁸=CR¹¹⁹;

J and G are each-N=CR¹⁵⁰-; and

I is absent.

According to still further features in the described preferred embodiments, D is-CR¹¹⁸=CR¹¹⁹;

E is absent;

F is-NR¹¹³-;

J and G are each-N=CR¹⁵⁰-; and

I is absent. According to still further features in the described preferred embodiments,

L and L^ are each C;

D is -N=CR¹²⁷-;

E is absent;

F is-NR¹¹³-; J is-N=CR¹⁵⁰-;

G is-NR¹³⁶-; and

I is-CR¹³⁴R¹³⁵.

According to still further features in the described preferred embodiments,

Li and 1^ are each C; D is-NR¹¹³-;

E is absent;

F is R¹²⁶ON-;

J is-N=CR¹⁵⁰-;

G is-NR¹³⁶-; and I is-CR¹³⁴R¹³⁵.

According to still further features in the described preferred embodiments,

Li and L₂ are each C;

D is-CR¹¹⁸=CR¹¹⁹; E is absent;

F is-NR¹¹³-;

J is-N=CR¹⁵⁰-;

G is-NR¹³⁶-; and I is-CR¹³⁴R¹³⁵.

According to still further features in the described preferred embodiments

Li and L₂ are each C;

D is-NR¹¹³-;

E is absent; F is-CR¹¹⁸=CR¹¹⁹;

J is-N=CR¹⁵⁰-;

G is-NR¹³⁶-; and

I is-CR¹³⁴R¹³⁵.

D is-NR¹¹³-;

E is absent;

F is-CR¹²⁶=N-;

J is-CR¹³⁴R¹³⁵-; G is-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-; and

I is-NR¹³⁶.

According to still further features in the described preferred embodiments,

D is-N=CR¹²⁷-; E is absent;

F is-NR¹¹³ -;

J is-CR¹³⁴R¹³⁵-;

G is-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-; and

I is-NR¹³⁶. According to still further features in the described preferred embodiments,

Li and L₂ are each C;

D is-CR^mCR¹¹²-;

E is absent; F is-CR¹²⁶=N-;

J is-CR¹³⁴R¹³⁵-;

G is-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-; and

D is-R¹²⁶ON -;

E is absent;

F is-CR^mCR¹¹²-; J is-CR¹³⁴R¹³⁵-;

G is-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-; and

I is-NR¹³⁶.

According to still further features in the described preferred embodiments,

D is-NR¹¹³-;

E is absent;

F is-CR¹²⁶=N-;

J and G are each CR¹¹⁸=CR¹¹⁹-; and

D is-N=CR¹²⁷-;

E is absent;

F is-NR¹¹³ -; J and G are each CR¹ ^CR¹¹⁹-; and

I is absent.

According to still further features in the described preferred embodiments,

Li and 1^ are each C;

D is-CR^mCR¹¹²-; E is absent;

F is-CR¹²⁶=N-;

J and G are each CR¹¹⁸=CR¹¹⁹-; and

Li and L₂ are each C;

D is-R¹²⁶ON -;

E is absent; F is-CR^mCR¹¹²-;

J and G are each CR¹¹⁸=CR¹¹⁹-; and

I is absent.

According to still further features in the described preferred embodiments the compound has the general Formula IN. According to still further features in the described preferred embodiments each of R³-R¹³ and of R¹⁵⁷-R¹⁶⁴ is independently selected from the group consisting of hydrogen, alkyl, hydrxyalkyl, carboxy, hydroxy, alkoxy, aryloxy, amido, thiohydroxy, thioalkoxy and carbohydrate.

According to still further features in the described preferred embodiments the compound has the general Formula N.

According to still further features in the described preferred embodiments Mi, Li, R¹⁸ and R¹⁹ are absent.

According to still further features in the described preferred embodiments,

M and L are each OO. According to still further features in the described preferred embodiments the compound is any of the compounds listed in Tables 1-5.

According to still further features in the described preferred embodiments wherein the modulating of the fat metabolism is effected by inhibiting Apobec-1 activity. According to still further features in the described preferred embodiments the modulating of the fat metabolism is by inhibiting apoB48 formation and/or secretion.

According to still further features in the described preferred embodiments at least the active site cavity of Apobec-1 is defined by amino acid coordinates 31-116 of Aρobec-1. According to still further features in the described preferred embodiments at least the active site cavity of Apobec-1 is defined by amino acid coordinates 1-142 of Aρobec-1. According to still further features in the described preferred embodiments the at least the active site cavity of Apobec-1 is defined by amino acid coordinates 59-98 of Apobec-1.

According to still further features in the described preferred embodiments the at least the active site cavity of Apobec-1 is defined by at least five amino acid residues present in the sequence defined by amino acid coordinates 59-98 of Apobec-

1.

According to still further features in the described preferred embodiments the at least five amino acid residues are as set forth in histidine 61, cysteine 93, cysteine 96, valine 62 and glutamate 63.

The present invention successfully addresses the shortcomings of the presently known configurations by providing compounds, compositions and methods for modulating fat metabolism.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

BRIEF DESCRIPTION OF THE DRAWINGS -

The invention is herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice. In the drawings: FIG. 1 is a schematic illustration showing amino acid sequence alignment between bacterial ECCDA (GenBank Accession No. PI 3652) and human Apobec-1 as generated using a two-step analysis involving primary sequence alignment and structural alignment, Green residues designate non homologous residues, red residues designate similar or homologous residues;

FIG. 2 is an image illustrating the three-dimensional model of a conformation of a human Apobec-1, interacted with 3-deazacytidine (one monomer is presented in green, the other monomer is presented in blue and two molecules of 3-deazacytidine are presented in both active sites as Van der Waals spheres); FIG. 3 is an image presenting the LUDI interactions of human Apobec-1, as generated by SBF (the atoms of the active site are represented by cylinders; the hydrogen bond donors are represented by blue and white, the hydrogen bonds acceptors are represented by red and gray; and the hydrophobic residues are represented by gray sphere). Also designated are some of the DAC coordinating moieties in the Apobec-1 protein;

FIG. 4 presents the three-dimensional structures of representative examples of potential Apobec-1 inhibitors, selected by screening the Maybridge database;

FIGs. 5a-c present the three-dimensional structures of representative examples of potential Apobec-1 inhibitors, selected by screening the NCI database; and FIG. 6 is a box diagram showing a computing platform 10 which can be used for practicing the present invention and which comprises computer readable medium, e.g., a data storage device 12, storing therein data 14 which is retrievable and processable by data processing unit 16 and the data or processed data can be displayed via a display such as a display screen 18 and/or a printer 20. FIGs. 7-132 present the coordinates of the three-dimensional model of a homodimer of human Apobec-1.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is of compounds, pharmaceutical compositions and methods which are useful in the treatment of diseases and disorders associated with fat metabolism. The present invention is further of methods of identifying compounds which are useful in the treatment of diseases and disorders associated with fat metabolism. Specifically, the present invention relates to compounds, pharmaceutical compositions and methods for treating disorders such as overweight, obesity, atherosclerosis, hypertension, Type II or non-insulin dependent diabetes mellitus, pancreatitis, hypercholestrosaemia, hypertriglyceridaema and hyperlipidemia. The principles and operation of the present invention may be better understood with reference to the drawings and accompanying descriptions.

Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.

Overweight and obesity are recognized health problems with approximately 97 million people considered clinically overweight or obese in the United States. Obesity and overweight are associated with a number of psychological and medical conditions including atherosclerosis, hypertension, Type II or non-insulin dependent diabetes mellitus, pancreatitis, hypercholestrosaemia, hypertriglyceridaema and hyperlipidemia.

Currently available treatment approaches utilize (i) appetite blockers, which include for example the NPY neuropeptide; (ii) satiety stimulators, which include, for example, the ob, db and agouti genes; (iii) energy or fatty acid burning agents, which include the UCPs; and (iv) fat absorption inhibitors such as the LP and MTP, described above.

The use of these targets is highly limited by the high level of redundancy in the biochemical pathways which control fat and energy metabolism and lack of tissue and functional specificity of obesity related genes. Thus, the above-described approaches frequently result in severe side effects, which render these inefficient and even life threatening. As such, new targets which can be more efficiently and safely used in methods for treating obesity are clearly needed. Chylomicrons are fat globules, which transport fat, and contain apiloprotein

B48 (apoB48) and are normally expressed in the intestine. The apoB48 protein is produced as a result of a post-transcriptional editing by the apoB mRNA editing protein termed, Apobec-1 (GenBank Accession No. NP_001635). The Apobec-1 editing protein deaminates cytidine to uridine, at position 6666 of the apoB mRNA, and produces a UAA in-frame stop codon [Chen, L. (1995). Biochemie 77:75-78;

Chen and Seeburg (1995), giving rise to a 48 KDa polypeptide, the apoB48.

Scientific American Science and Medicine 2:68-77]. It has been previously suggested (see in FR 97 16655 and FR 97 04388 and

U.S. Pat. No. 6,210,888) that selective inhibition of Apobec-1 activity, would inhibit the formation of fat-transporting chylomicrons and, as a consequence, reduce absorption of fatty acids.

While reducing the present invention to practice and while searching for novel therapeutic agents which can be used to treat clinical conditions associated with abnormal fat metabolism, the present inventors identified a set of coordinates which define the active site cavity of Apobec-1 as well as the location and number of pharmacophore interacting moieties therein, thus allowing, for the first time, identification of specific and efficacious Apobec-1 inhibitors, which can be used to modulate fat metabolism in an individual.

As is illustrated in the Examples section which follows, the present inventors were able to elucidate, through laborious computational experimentation, the three dimensional structure of the active site cavity of Apobec-1. Using this structural information the three dimensional structure of potential Apobec-1 inhibitors (pharmacophores) was constructed using a Structure Based Focusing (SBF) procedure, to obtain a general formula of potential Apobec-1 inhibitors. Information derived form this general formula was used to identify candidate compounds capable of modulating fat metabolism.

Thus, according to one aspect of the present invention there is provided a method of identifying a candidate compound for modulating fat metabolism associated with Apobec-1 activity.

As used herein the phrase "candidate compound' refers to a compound which is capable of inhibiting Apobec-1 activity uncovered using the methodology described herein. A candidate compound of the present invention is a compound which is capable of modulating fat metabolism to a degree which is beneficial for treatment. Candidate compounds according to this aspect of the present invention can bind to one or more active sites (i.e. functional domains) of Apobec-1. Without being bound by theory, candidate compounds according to this aspect of the present invention can be molecules which act as competitive inhibitors, non- competitive inhibitors, molecules which interfere with Apobec-1 binding of apobec-1 associated proteins (e.g., microsomal triglyceride transfer protein (MTTP) or apobec- 1 -interacting protein (ABBP-1)] or interfere with Apobec-1 dimerization by binding at the interface between the two Apobec-1 monomers.

Thus, an active site (cavity) as defined herein includes any site which participates in any of the above described Apobec-1 activities or interactions.

As used herein the phrase "modulating fat metabolism" refers to increasing or decreasing transport of fat across the intestine. As used herein the term "fat' refers to glycerol esters of saturated fatty acids such as triglycerides and fat-like substances such as steroid alcohol such as cholesterol.

As used herein the term 'M biting Apobec-1 activity" refers to inhibiting or partially inhibiting the cytidine deaminase activity of Apobec-1, preferably human Apobec-1, such as set forth in GenBank Accession No. NP_001635. It will be appreciated that due to sequence homology shared between Apobec-1 and other members of this protein family, compounds of the present invention may serve as inhibitors of Apobec-1 related proteins, which are implicated in hyperproliferative diseases such as cancer and psoriasis. The method of this aspect of the present invention is effected by obtaining a set of coordinates which define the three dimensional structure of at least the active site cavity of Apobec-1 and computationally identifying a compound which specifically binds the active site cavity of Apobec-1, to thereby identify candidate compounds which modulate fat metabolism by inhibiting Apobec-1 activity. As is mentioned hereinabove, the "active site cavity of Apobec-1" refers to at least one functional domain of Apobec-1 (i.e., when in monomeric or dimeric form). Preferably, the active site cavity of apobec-1 is the zinc-dependent deaminase domain and/or the RNA binding domain, which are positioned within the sequence defined by amino acid coordinates 1-42 of Apobec-1, preferably within the sequence defined by amino acid coordinates 31-116 of Apobec-1, even more preferably within the sequence defined by amino acid coordinates 59-98 of Apobec-1. The active site of the Apobec-1 dimer is shown in Figure 2. Other functional domains of Apobec-1 include a leucine rich region, an RG region and an Apobec-1 complementation region, which depends on ACF binding to both Apobec-1 and connected RNA sequence. Further description of these domains and approaches suitable for inhibition thereof is provided by GeneCard GC12M007970 (available in GeneCards www.rzpd.de/cards/index.html).

When utilized for identifying inhibitors, the active site can be represented by the three-dimentional structure and/or the pharmacophore-interacting moieties

(i.e.,amino acid residues or specific atoms thereof) present in or around the active site.

Further description of these pharmacophore-interacting moieties is provided hereinunder (see Figure 3).

Typically, obtaining the set of atomic coordinates which define the three dimensional structure of the active site cavity of an enzyme (e.g., Apobec-1) can be effected using various approaches which are well known in the art. Examples include, but are not limited to, neutron diffraction, or by nuclear magnetic resonance (NMR) [See, e.g., Moore, W. J., Physical Chemistry, 4.sup.th Edition, Prentice-Hall, N . (1972)], and X-ray crystallography which is preferred for obtaining the secondary and tertiary structure information, which requires detailed information about the arrangement of atoms within a protein.

X-ray crystallography is effected by exposing crystals to an X-ray beam and collecting the resultant X-ray diffraction data. This process usually involves the measurements of many tens of thousands of data points over a period of one to several days depending on the crystal form and the resolution of the data required. The crystals diffract the rays, creating a geometrically precise pattern of spots recorded on photographic film or electronic detectors. The distribution of atoms within the crystal influences the pattern of spots. The quality of protein crystals is determined by the ability of the crystal to scatter X-rays of wavelengths (preferably 1.0-2.8. A) suitable to determine the atomic coordinates of the macromolecule. The measure of the quality is determined as a function of the highest angle of scatter (the ultimate or intrinsic resolution) and according to Bragg's Law: nλ = 2d sinø (where θ is the angle of incidence of the reflected X-ray beam, d is the distance between atomic layers in a crystal, λ is the wavelength of the incident X-ray beam, and n is an integer), d may be determined, and represents the resolution of the crystal form in angstroms. Thus, this measurement is routinely used to judge the ultimate usefulness of protein crystals. Group theory shows that there are 230 unique ways in which chemical substances, proteins or otherwise, may assemble in three-dimensional to form crystals. These are called the 230 "space groups." The designation of the space group in addition to the unit cell constants (which define the explicit size and shape of the cell which repeats periodically within the crystal) is routinely used to uniquely identify a crystalline substance. Certain conventions have been established to ensure the proper identification of crystalline materials and these conventions have been set forth and documented in the International Tables for Crystallography, incorporated herein by reference. U.S. Pat. No. 6,093,573 describes in details X-ray crystallography. Alternatively, a three dimensional structure of a polypeptide of interest can be constructed using computer-based protein modeling techniques (such as described in the Examples section which follows). In such cases, the three dimensional structure of a protein is solved by finding target sequences that are most compatible with profiles representing the structural environments of the residues in known three- dimensional protein structures (See, e.g., U.S. Pat. No. 5,436,850).

In another technique, the known three-dimensional structures of proteins in a given family are superimposed in-order to define the structurally conserved regions of that protein family. This protein modeling technique also uses a known three- dimensional structure of a homologous protein to approximate the structure of a polypeptide of interest (See e.g., U.S. Pat. Nos. 5,557,535; 5,884,230; and 5,873,052). Conventional homology modeling techniques have been used routinely to build models of proteases and antibodies [Sowdhamini et al., Protein Engineering 10:207, 215 (1997)]. Comparative approaches can also be used to develop three- dimensional protein models when the protein of interest has poor sequence identity to template proteins. In some cases, proteins fold into similar three-dimensional structures despite having very weak sequence identities. For example, the three- dimensional structures of a number of helical cytokines fold in similar three- dimensional topology in spite of low sequence homology.

Alternatively, elucidating the three dimensional structure of proteins can be effected using Multiple Sequence Threading (MST) in which structural equivalences are deduced from the threading output using the distance geometry program DRAGON that constructs a low resolution model. A full-atom representation is then constructed using a molecular modeling package such as QUANTA. Regardless of the method used, structural data obtained is preferably recorded on a computer readable medium so as to enable data manipulation and construction of computational models. As used herein, "computer readable medium" refers to any medium which can be read and accessed directly by a computer. Such media include, but are not limited to: magnetic storage media, such as floppy discs, hard disc storage medium, and magnetic tape; optical storage media such as optical discs or CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media. Selection and use of appropriate storage media is well within the capabilities of one of ordinary skill in the art. As used herein, "recorded" refers to a process of storing information on computer readable medium.

It will be appreciated that a number of data storage devices can be used for creating a computer readable medium having recorded thereon the structural data of the present invention. The choice of the data storage structure is typically based on the means chosen to access the stored information. In addition, a variety of data processor programs and formats can be used to store the data information of the present invention on computer readable medium. The sequence information can be represented in a word processing text file, formatted in commercially-available software such as WordPerfect and MICROSOFT Word, or represented in the form of an ASCII file, stored in a database application, such as DB2, Sybase, Oracle, or the like.

According to preferred embodiments of ^"this aspect of the present invention, the coordinate data used to define the structure of the active site cavity of Apobec-1 or a portion thereof is derived from the set of coordinate data set forth in Figures 7-132 which represent Apobec-1 complexed with the DAC inhibitor.

It will be appreciated that structure models of the present invention are preferably generated by a computing platform, which generates a graphic output of the models via a display generating device such as screen or printer. The computing platform generates graphic representations of atomic structure models via a processing unit which processes structure coordinate data stored in a retrievable format in the data storage device (such as described above, see Figure 6).

Suitable software applications, well known to those of skill in the art, which may be used by the processing unit to process structure coordinate data so as to provide a graphic output of three-dimensional structure models generated therewith via display include RIBBONS (Carson, M., 1997. Methods in Enzymology 277, 25),

O (Jones, TA. et al, 1991. Acta Crystallogr A47, 110), DINO (DINO: Visualizing

Structural Biology (2001) http://www.dino3d.org); and QUANTA, CHARMM, INSIGHT, SYBYL, MACROMODE, ICM, MOLMOL, RASMOL and GRASP

(reviewed in Kraulis, J., 1991. Appl Crystallogr. 24, 946).

As mentioned hereinabove, once the three dimensional structure of at least the active site cavity of Apobec-1 is obtained, compounds which at least spatially fit thereto are identifiable. This is preferably effected using Rational Drug Design (RDD).

RDD is a potent means of identifying enzyme inhibitors which, for example, has notably been used to identify HIV protease (Lam et al, 1994. Science 263, 380; Wlodawer et al, 1993. Ann Rev Biochem. 62, 543; Appeli, 1993. Perspectives in Drug Discovery and Design 1, 23; Erickson, 1993. Perspectives in Drug Discovery and Design 1, 109), and bcr-abl tyrosine kinase inhibitors (Mauro MJ. et al, 2002. J Clin Oncol. 20, 325-34) used to provide the first effective pharmacological cures for human acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HJN)), and a human cancer (chronic myeloid leukemia), respectively. One approach to identify a putative inhibitor via rational drug design is by screening a chemical structure database ('3D database"), using software employing 'Scanner" type algorithms. Such software applications utilize atomic coordinates defining the three-dimensional structure of a binding pocket of a molecule and of a chemical structure stored in the database to computationally model the "docking" of the screened chemical structure with the binding pocket so as to qualify the binding of the binding pocket with the chemical structure. Iterating this process with each of a plurality of chemical structures stored in the database therefore enables computational screening of such a plurality to identify a chemical structure potentially having a desired binding interaction with the binding pocket, and hence the putative inhibitor. Examples of suitable chemical structure databases for identifying the candidate molecules of the present invention include ISIS (MDL Information Systems, San Leandro, http://www.molinfo.com), MACCS-3D (Martin, Y. C, 1992. J. Med. Chem. 35, 2145-2154), The Cambridge Structural Database (CSD; ht1n://www.ccdc.cam.ac.uk/prods/csd/csd.html), Fine Chemical Database (reviewed in

Rusinko A., 1993. Chem Des Auto. News 8, 44-47), and the NCBI's Molecular

Modeling DataBase: MMDB; http://www.ncbi.nlm.nih.gov/Strucrure/MMDB/mmdb.shtml. Other libraries of chemicals are commercially available from, for example,

Merck, Glaxo Welcome, Bristol Meyers Squib, Monsanto/Searle, Eli Lilly, Novartis and Pharmacia UpJohn.

Alternatively, identifying the candidate compounds can be effected using de novo rational drug design, or via modification of a known chemical structure. In such case, software comprising "builder" type algorithms utilizes a set of atomic coordinates defining a three-dimensional structure of the binding pocket and the three- dimensional structures of basic chemical building blocks to computationally assemble a putative inhibitor. Such an approach may be employed to structurally refine a putative inhibitor identified, for example, via chemical database screening as described above.

Ample guidance for performing rational drug design by utilizing software employing such "scanner" and "buildef ' type algorithms is available in the literature (see, for example, Halperin I. et al, 2002. Proteins 47, 409-43; Gohlke H. and Klebe G., 2001. Curr Opin Struct Biol. 11, 231-5; Zeng J., 2000. Comb Chem High Throughput Screen. 3, 355-62; and RACHEL: Theory of drug design, http://www.newdragdesign.corrι/Rachel_Theory.htm#Software). Additional guidance is provided hereinbelow and in the Examples section which follows.

Criteria employed by software programs used in rational drug design to qualify the binding of screened chemical structures with binding pockets include gap space, hydrogen bonding, electrostatic interactions, van der Waals forces, hydrophilicity/hydrophobicity, etc. Generally, the greater the contact area between the screened molecule and the binding region of the Apobec-1, the lower the steric hindrance, the lower the "gap space", the greater the number of hydrogen bonds, and the greater the sum total of the van der Waals forces between the screened molecule and the apoB48 binding region of the Apobec-1 protein, the greater will be the capacity of the screened molecule to bind with the apoB48binding region of Apobec- 1. The "gap space" refers to unoccupied space between the van der Waals surface of a screened molecule positioned within a binding pocket and the surface of the binding pocket defined by amino acid residues in the binding pocket. Gap space may be identified, for example, using an algorithm based on a series of cubic grids surrounding the docked molecule. Gap space represents volume that could advantageously be occupied by modifying a molecule positioned within the apoB48 binding region of the Apobec-1.

Contact area between compounds may be directly calculated from the coordinates of the compounds in docked conformation using the MS program (Connolly ML., 1983. Science 221, 709-713).

Suitable software employing "scanner" type algorithms include, for example, docking software such as GRAM, DOCK, or AUTODOCK (reviewed in Dunbrack et al, 1997. Folding and Design 2, 27), AFFINITY software of the INSIGHTII package (Molecular Simulations Inc., 1996, San Diego, Calif.), GRID (Goodford PJ., 1985. "A Computational Procedure for Determining Energetically Favorable Binding Sites on Biologically Important Macromolecules", J. Med. Chem. 28, 849-857; GRID is available from Oxford University, Oxford, UK), and MCSS (Miranker A. and Karplus M., 1991. "Functionality Maps of Binding Sites: A Multiple Copy Simultaneous Search Method", Proteins: Structure Function and Genetics 11, 29-34; MCSS is available from Molecular Simulations, Burlington, Mass.).

The AUTODOCK program (Goodsell DS. and Olson AJ., 1990. Proteins: Struct Funct Genet. 8, 195-202; available from -Scripps Research Institute, La Jolla, Ca.) helps in docking screened molecules to binding pockets in a flexible manner using a Monte Carlo simulated annealing approach. The procedure enables a search without bias introduced by the researcher which can influence orientation and conformation of a screened molecule in the targeted binding pocket.

The DOCK program (Kuntz ID. et al, 1982. J Mol Biol. 161, 269-288; available from University of California, San Francisco), is based on a description of the negative image of a space-filling representation of the binding pocket, and includes a force field for energy evaluation, limited conformational flexibility and consideration of hydrophobicity in the energy evaluation.

Modeling or docking may be followed by energy minimization with standard molecular mechanics force fields or dynamics with programs such as CHARMM (Brooks BR. et al, 1983. J Comp Chem. 4, 187-217) or AMBER (Weiner SJ. et al,

1984. J Am Chem Soc. 106, 765-784).

As used herein, "minimization of energy" means achieving an atomic geometry of a chemical structure via systematic alteration such that any further minor perturbation of the atomic geometry would cause the total energy of the system, as measured by a molecular mechanics force-field, to increase. Minimization and molecular mechanics force fields are well understood in computational chemistry (for example, refer to Burkert U. and Allinger NL., "Molecular Mechanics", ACS

Monograph 177, pp. 59-78, American Chemical Society, Washington, D.C. (1982)). Programs employing 'builder" type algorithms include LEGEND (Nishibata Y. and Itai A., 1991. Tetrahedron 47, 8985; available from Molecular Simulations, Burlington, Mass.), LEAPFROG (Tripos Associates, St. Louis, Mo.), CAVEAT (Bartlett, PA. et al, 1989. Special Pub Royal Chem Soc. 78, 182-196; available from University of California, Berkeley), HOOK (Molecular Simulations, Burlington, Mass.), and LUDI (Bohm HJ., 1992. J. Comp Aid Molec Design 6, 61-78; available from Biosym Technologies, San Diego, Calif. See Examples section which follows).

The CAVEAT program suggests possible binding molecules based on desired bond vectors. The HOOK program proposes docking sites by using multiple copies of functional groups in simultaneous searches. LUDI is a program based on fragments rather than on descriptors which proposes somewhat larger fragments as possible matches with a binding pocket and scores its hits based on geometric criteria taken from the Cambridge Structural Database (CSD), the Protein Data Bank (PDB) and on criteria based on binding data. LUDI may be advantageously employed to calculate the inhibition constant of a docked chemical structure. Inhibition constants (Ki values) of compounds in the final docking positions can be evaluated using LUDI software.

Optionally, the candidate molecule is identified by further determining the position and orientation of at least one pharmacophore interacting moiety in the active site cavity of Apobec-1 and identifying a compound which fits both structurally and chemically to the three dimensional structure of the active site cavity.

This is preferably effected by "fitting" a compound capable of inhibiting Apobec-1 [e.g., 3-deazacytidine (DAC)] into the three-dimensional structure of an active site cavity (as illustrated in the Examples section which follows), to thereby identify the position and orientation of one or more pharmacophore interacting moieties in the active site cavity.

The fitting scheme described above allows to select the most relevant moieties of the active site. Representative examples of pharmacophore interacting moieties include hydrogen bonds donor and acceptor moieties, hydrophobic moieties and the like.

Preferably, the pharmacophore interacting moieties which participate in inhibitory binding to the catalytic site of Apobec-1 are Val62, Cys96, Cys93 and

His61. Additional pharmacophore interacting moieties can be identified using the methodologies described in the examples section, combined with the PDB data of Figures 7-132 and the chemical structure presented in Figure 3. Thus, when screening compounds for capability of inhibiting Apobec-1, binding of a putative inhibitor to at least one of these moieties is preferably qualified.

Once one or preferably several of such moeties are identified combinatorial combinations of these moieties is preferably constructed in the context of the active site structure, and the identification of the compound is performed based on one or more of these combinations. Further description of this design approach is provided in the Examples section which follows.

During or following rational drug design, docking of an intermediate chemical structure or of the putative inhibitor with the binding pocket may be visualized via structural models, such as three-dimensional models thereof displayed on a computer screen, so as to advantageously allow user intervention during the rational drug design to optimize a chemical structure.

Software programs useful for displaying such three-dimensional structural models, include RIBBONS (Carson, M., 1997. Methods in Enzymology 277, 25), O (Jones, TA. et al, 1991. Acta Crystallogr. A47, 110), DINO (DINO: Visualizing Structural Biology (2001) http://www.dino3d.org); and QUANTA, INSIGHT, SYBYL, MACROMODE, ICM, MOLMOL, RASMOL and GRASP (reviewed in Kraulis, J., 1991. Appl Crystallogr. 24, 946). Other molecular modeling techniques may also be employed in accordance with this invention (for example, refer to: Cohen NC. et al, 1990. "Molecular Modeling Software and Methods for Medicinal Chemistry", J. Med. Chem. 33, :883- 894; Navia M. A. and Murcko M. A., 1992. 'The Use of Structural Information in Drug Design", Current Opinions in Structural Biology 2, 202-210). For example, where the structures of test compounds are known, a model of the test compound may be superimposed over the model of the structure of the invention. Numerous methods and techniques which are well known in the art can be used for performing this step (for example, refer to: Farmer P. S., "Drug Design", Ariens EJ. (ed.), Vol. 10, pp 119—

143 (Academic Press, New York, 1980); U.S. Pat. No. 5,331,573; U.S. Pat. No.

5,500,807; Verlinde C, 1994. Structure 2, 577-587; and Kuntz ID., 1992. Science

257, 1078-108).

Using a rational drug design approach, such as that described in the Examples section which follows, the present inventors uncovered that candidate compounds having the general Formulae I, II, III, IV and V (described hereinafter) can be used to modulate fat metabolism by inhibiting Apobec-1 activity.

The compounds of the present invention can therefore be a part of five different families, as depicted in Formulae I-V, as follows:

Formula I Formula II

Formula III

Formula TV R¹⁴-M-R¹⁵-L-R¹⁶-Mι-R¹⁸-L R¹⁹

Formula N

or a pharmaceutically acceptable salt thereof, wherein,

A and B are each independently Ν or CRa;

W is -CR²⁰R²¹-CR²²R²³-, -CR²⁴=CR²⁵-, -R²⁶R²⁷C-ΝR²⁸-, -R²⁹N-CR³⁰R³¹-, - R³²ON-, -N=CR³³-, -N=N-, -NR³⁴-NR³⁵-, R³⁶N-CR³⁷= or =R³⁸C-NR³⁹, or absent;

Q -CR⁴⁰R⁴¹-, -NR⁴²-, -CR^-CR^R⁴⁶-, -CR ⁷=CR⁴⁸-, R⁴⁹R⁵⁰C-NR⁵¹-, - R⁵²N-CR⁵³R⁵⁴, -R⁵⁵ON-, -N=CR⁵⁶-, -N=N-, -NR⁵⁷-NR⁵⁸-, R⁵⁹N-CR⁶⁰= or =R⁶¹C- NR⁶², or absent;

V is O, S, Pd, -NR⁶⁹, -CR⁷⁰R⁷¹-, -R⁷²R⁷³C-CR⁷⁴R⁷⁵-, -R⁷⁶R⁷⁷C-CR⁷⁸R⁷⁹- CR⁸⁰R⁸¹-, -R⁸²R⁸³C-CR⁸⁴R⁸⁵-CR⁸⁶R⁸⁷-CR⁸⁸R⁸⁹-, -R⁹⁰C=CR⁹¹-, -R⁹²R⁹³C-NR⁹⁴-

_CR109_R11Q.

D, E and F are each independently -CR^1UR¹¹²-, -NR¹¹³-, O, S, -CR¹¹⁴R¹¹⁵- CR¹¹⁶R¹¹⁷-, -CR¹¹⁸=CR¹¹⁹-, R¹²⁰R¹²¹C-NR¹²²-,- -R¹²³N-CR¹²⁴R¹²⁵-, -R¹²⁶ON-, - N=CR¹²⁷-, -N=N-, -NR¹²⁸-NR¹²⁹-, R¹³⁰N-CR¹³¹= or =R¹³²C-NR¹³³, or absent;

G, I and J are each independently-CR¹³⁴R¹³⁵-, -NR¹³⁶-, -CR¹³⁷R¹³⁸-CR¹³⁹R¹⁴⁰-, -CR¹⁴¹=CR¹⁴²-, -R¹⁴³R¹⁴⁴C-NR¹⁴⁵-, -R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-, -R¹⁴⁹ON-, -N=CR¹⁵⁰-, -N=N- , -NR¹⁵¹-NR¹⁵²-, R¹⁵³N-CR¹⁵⁴= or =R¹⁵⁵C-NR¹⁵⁶, or absent;

Li and L₂ are each independently C, CRc or N;

T is-CR¹⁵⁷R¹⁵⁸R¹⁵⁹,-CR¹⁶⁰R¹⁶¹-CR¹⁶²R¹⁶³R¹⁶⁴ or-R¹⁶⁵;

M is OO, S=O, P=O, C=S, C=N-R¹⁶⁶, S=N-R¹⁶⁷, N=N-R¹⁶⁸ or OC-R¹⁶⁹; Mi, L and Li are each independently C=O, S=O, P=O, OS, ON-R¹⁷⁰, S=N-

R¹⁷¹, N=N-R¹⁷² or OC-R¹⁷³ or absent; and each of Ra, Rb, Re and R^!-R¹⁷³ of the above described general formula is independently selected from the group consisting of hydrogen, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, 0- thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, trihalomethanesulfonamido, guanyl, guanidino, carbohydrate, and amino, or, alternatively, at least two of R², R³ and R²⁰-R⁶² form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula I, at least two of R⁶³-R¹¹⁰ form at least one three-, four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula II, at least two of R^ιπ-R¹³³ form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring and/or at least two of R¹³ -R¹⁵ form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Foπnula III, and at least two of R³-R¹³ and/or of R¹⁵⁷-R¹⁶⁴ form a three-, four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula IN.

Preferred compounds of the class of compounds described by Formula I of the present invention, include, without limitation, compounds wherein: A and B are each CRa; W is-Ν=CR³³-; and Q is -CR⁴⁷=CR⁴⁸-; A is N; B is CRa; W is^-CR³³-; and Q is -CR⁴⁷=CR⁴⁸-; A is CRa; B is N; W is-R³²ON-; and Q is-R⁵⁵ON; A and B are each CRa; W is-R³²ON-; and Q is -^⁴⁹R⁵⁰C-NR⁵¹-; A and B are each CRa; W is-R²⁶R²⁷C-NR²⁸-; and Q is-R⁴⁹R⁵⁰C-NR⁵¹-; A and B are each CRa; W is -CR²⁴=CR²⁵; and Q is -CR ⁷=CR⁴⁸; A and B are each CRa; W is =N=CR³³-; and Q is NR⁴²; A and B are each CRa; W is-R³²ON-; and Q is NR⁴²; A and B are each CRa; W is-R²⁶R²⁷C-NR²⁸-; and Q is NR⁴²; A is N; B is CRa; W is -CR²⁰R²¹-CR²²R²³-; and Q is NR⁴²; A and B are each N; W is -CR²⁰R ¹-CR²²R²³-; and Q is NR⁴²; A is N; B is CRa; W is R²⁹N-CR³⁰R³¹; and Q is-CR⁴⁰R⁴¹; A and B are each N; W is -R²⁹N-CR³⁰R³¹; and Q is-CR⁴⁰R⁴¹; A and B are each CRa; W is-R²⁶R²⁷C-NR²⁸-; and Q is-CR⁴⁰R⁴¹; A is N; B is CRa; W is-CR²⁰R²¹-CR²²R²³-; and Q is-CR⁴⁰R⁴¹;

A and B are each N; W is -R²⁹N-CR³⁰R³¹; and Q is-CR⁴³R⁴⁴-CR⁴⁵R⁴⁶.

Some of these compounds are pyrimidine, pyridine, benezene and imidazole derivatives. Such compounds preferably include at least one carbohydrate moiety, the nature of which is defined hereinbelow.

Preferably, the compounds described above also include, without limitation, compounds wherein:

V is-R⁷²R⁷³C-CR⁷⁴R⁷⁵-; U is absent, X and Z are each -CR⁶³R⁶⁴-; and Y is O, or X and Z are each oxygen; and Y is -CR⁶³R⁶⁴-. Such compounds are either tetrahydrofurane derivatives or dioxolane derivatives, being preferably substituted by hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl groups.

The class of compounds described by Formula II of the present invention include compounds wherein: V is -R⁸²R⁸³C-CR⁸⁴R⁸⁵-CR⁸⁶R⁸⁷-CR⁸⁸R⁸⁹-; U is absent, and X and Z are each -

CR⁶³R⁶⁴-; and Y is O, or X and Z are each oxygen; andY is -CR⁶³R⁶⁴-.

These compounds are either terahydropyrane derivatives or 1,3-dioxane derivatives.

The class of compounds described by Formula III of the present invention, include, without limitation, compounds wherein:

Li and L₂ are each C; D is N; E is -CR^{π ι}R¹¹²-; F is -NR¹¹³-; J and G are each - N=CR¹⁵⁰-; and I is absent.

Li and L₂ are each C; D is -N=CR¹²⁷-; E is absent; F is -NR¹¹³-; J and G are each- N=CR¹⁵⁰-; and I is absent. Li and L₂ are each C; D is -NR¹¹³-; E is absent; F is -R¹²⁶ON-; J and G are each - N=CR¹⁵⁰-; and I is absent.

D is -NR¹¹³-; E is absent; F is -CR¹¹⁸=CR¹¹⁹; J and G are each-N=CR¹⁵⁰-; and I is absent.

D is -CR¹¹⁸=CR¹¹⁹; E is absent; F is -NR¹¹³-; J and G are each -N=CR¹⁵⁰-; and I is absent.

Li and L₂ are each C; D is -N=CR¹²⁷-; E is absent; F is-NR¹¹³-; J is-N=CR¹⁵⁰-; G is- NR¹³⁶-; and I is-CR¹³ R¹³⁵. Li and L₂ are each C; D is-NR¹¹³-; E is absent; F is R¹²⁶ON-; J is-N=CR¹⁵⁰-; G is- NR¹³⁶-; and I is-CR¹³ R¹³⁵.

Li and L₂ are each C; D is-CR¹¹⁸=CR¹¹⁹; E is absent; F is-NR¹¹³-; J is-N=CR¹⁵⁰-; G is-NR¹³⁶-; and I is-CR¹³⁴R¹³⁵. Li and L₂ are each C; D is -NR¹¹³-; E is absent; F is -CR¹¹⁸=CR¹¹⁹; J is -N=CR¹⁵⁰-; G is-NR¹³⁶-; and I is-CR¹³⁴R¹³⁵. Li and L₂ are each C; D is-NR¹¹³-; E is absent; F is-CR¹²⁶=N-; J is^CR¹³⁴R¹³⁵-; G is-

Li and L₂ are each C; D is-N=CR¹²⁷-; E is absent; F is-NR¹¹³ -; J is-CR¹³⁴R¹³⁵-; G is 4l^14oN-CR¹⁴⁷R¹⁴⁸-; and I is-NR¹³⁶.

Li and L₂ are each C; D is-CR^luCR¹¹²-; E is absent; F is-CR¹²⁶=N-; J is-CR¹³⁴R¹³⁵-;

G is-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-; and I is-NR¹³⁶.

Li and L₂ are each C; D is-R¹²⁶ON -; E is absent; F is-CR^mCR¹¹²-; J is-CR¹³⁴R¹³⁵-

; G is-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-; and I is-NR¹³⁶. Li and L₂ are each C; D is -NR¹¹³-; E is absent; F is -CR¹²⁶=N-; J and G are each

CR¹¹⁸=CR¹¹⁹-; and I is absent.

Li and 1^ are each C; D is -N=CR¹²⁷-; E is absent; F is -NR¹¹³ -; J and G are each

CR¹¹⁸=CR¹¹⁹-; and I is absent.

Li and L₂ are each C; D is-CR^luCR¹¹²-; E is absent; F is-CR¹²⁶=N-; J and G are each CR¹¹⁸=CR¹¹⁹-; and I is absent.

Li and L₂ are each C; D is -R¹²⁶ON -; E is absent; F is -CR^mCR¹¹²-; J and G are each CR¹¹⁸=CR¹¹⁹-; and I is absent.

The class of compounds described by Formula IN of the present invention include, without limitation, alkylenes which are substituted, inter alia, by alkyl, hydrxyalkyl, carboxy, hydroxy, alkoxy, aryloxy, amido, thiohydroxy, thioalkoxy and carbohydrate.

Preferred compounds that have the general Formula N according to the present invention include, without limitation, compounds wherein Mi, L_l5 R¹⁸ and R¹⁹ are absent and M and L are each OO. Such compounds often form a configuration which mimic a nuclotide.

It will be appreciated by one of skills in the art that the feasibility of each of the substituents (Ra, Rb, Re and R^R¹⁷³) to be located at the indicated positions depends on the valency and chemical compatibility of the substituent, the substituted position and other substituents. Hence, the present invention is aimed at encompassing all the feasible substituents for any position.

As used herein in the specification and in the claims section that follows, the term "alkyl" refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms.

Whenever a numerical range; e.g., "1-20", is stated herein, it implies that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. More preferably, the alkyl is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, unless otherwise indicated, the alkyl is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted. When substituted, the substituent group can be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, trihalomethanesulfonamido, guanyl, guanidino, carbohydrate, and amino. A "cycloalkyl" group refers to an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group wherein one of more of the rings does not have a completely conjugated pi electron system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, cycloheptane, cycloheptatriene, and adamantane. A cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent group can be, for example, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, trihalomethanesulfonamido, guanyl, guanidino, carbohydrate, and amino. An "alkenyl" group refers to an alkyl group which consists of at least two carbon atoms and at least one carbon-carbon double bond.

An "aryl" group refers to an all-carbon monocyclic or fused-ring polycyclic

(i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted. When substituted, the substituent group can be, for example, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, trihalomethanesulfonamido, guanyl, guanidino, carbohydrate, and amino.

A "heteroaryl" group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system. Examples, without limitation, of heteroaryl groups include pyrrole, furane, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoqumoline and purine. The heteroaryl group may be substituted or unsubstituted. When substituted; the substituent group can be, for example, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O- carboxy, sulfonamido, trihalomethanesulfonamido, guanyl, guanidino, carbohydrate, and amino,

A "heteroalicyclic" group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. The heteroalicyclic may be substituted or unsubstituted. When substituted, the substituted group can be, for example, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O- carboxy, sulfonamido, trihalomethanesulfonamido, guanyl, guanidino, carbohydrate, and amino. Representative examples are piperidine, piperazine, tetrahydro furane, tetrahydropyrane, morpholino and the like.

A "hydroxy" group refers to an -OH group.

An "azo" group refers to a -N=N group.

An "alkoxy" group refers to both an -O-alkyl and an -O-cycloalkyl group, as defined herein.

An "aryloxy" group refers to both an -O-aryl and an -O-heteroaryl group, as defined herein.

A "thiohydroxy" group refers to an -SH group.

A "thioalkoxy" group refers to both an -S-alkyl group, and an -S-cycloalkyl group, as defined herein.

An "thioaryloxy" group refers to both an -S-aryl and an -S-heteroaryl group, as defined herein.

A "carbonyl" group refers to a -C(=O)-R' group, where R" is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) or heteroalicyclic (bonded through a ring carbon) as defined herein.

An "aldehyde" group refers to a carbonyl group, where R' is hydrogen.

A "thiocarbonyl" group refers to a -C(=S)-R" group, where R" is as defined herein for R'.

A "C-carboxy" group refers to a -C(=O)-O-R" groups, where R" is as defined herein.

An "O-carboxy" group refers to an R"C(=O)-O- group, where R" is as defined herein.

A "carboxy" group refers to a =O group. A "carboxylic acid" group refers to a C-carboxyl group in which R" is hydrogen.

A "halo" group refers to fluorine, chlorine, bromine or iodine.

A "trihalomethyl" group refers to a -CX group wherein X is a halo group as defined herein.

A "trihalomethanesulfonyl" group refers to an

group wherein X is a halo group as defined herein.

A "sulfinyl" group refers to an -S(=O)-R" group, where R"is as defined herein. A "sulfonyl" group refers to an

group, where R" is as defined herein.

An "S-sulfonamido" group refers to a

group, with R' and R"as defined herein.

An "N-sulfonamido" group refers to an R'S(=O)2-NR" group, where R' and R" are as defined herein. A "trihalomethanesulfonamido" group refers to an X CS^O^N - group, where R' and X are as defined herein.

An "O-carbamyl" group refers to an -OC(=O)-NR'R'' group, where R' and R" are as defined herein.

An "N-carbamyl" group refers to an R"OC(=0)-NR'- group, where R' and R" are as defined herein.

An "O-thiocarbamyl" group refers to an "-OC(=S)-NR'R" group, where R' and R" are as defined herein.

An ''N-thiocarbamyl" group refers to an R"OC(=S)NR'- group, where R' and R" are as defined herein. An "Amino" group refers to an-NR'R" group where R' and R" are as defined herein.

A "C-amido" group refers to a -C(=O)-NR'R^M group, where R' and R" are as defined herein.

An "N-amido" group refers to an R'C(=O)-NR" group, where R' and R" are as defined herein.

An "urea" group refers to an -NR'C(=O)-NR"R'⁹ group, where R' and R" are as defined herein and R'" is defined as either R' or R". A "guanidino" group refers to an-R'NC(=N)-NR"R^w group, where R\ R" and R" are as defined herein.

A "guanyl" group refers to an R'R^*NC(=N)- group, where R' and R" are as defined herein. A "nitro" group refers to an -NO2 group.

A "cyano" group refers to a -ON group.

The term "phosphonyl" describes a -O-P(=O)(OR')- group, with R' as defined hereinabove.

The term 'phosphinyl" describes a -PR'- group, with R' as defined hereinabove. The term "phosphonium" is a -P⁺R'R", where R' and R" are as defined hereinabove.

The term "ketoester" describes a -C(=O)-C(=O)-O- group.

The term "thiourea" describes a -NR'-C(=S)-NR'- group, with R' and R" as defined hereinabove. The term 'hydrazine?' described a NR'-NR" group, with R and R" as defined hereinabove.

The term "carbohydrate" describes a molecule that includes a combination of carbons, hydrogens and oxygens. The carbohydrate can be cyclic or linear, saturated or unsaturated and sunstituted and unsubstituted. When substituted, the substituent can be, for example, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N- amido, C-carboxy, O-carboxy, sulfonamido, trihalomethanesulfonamido, guanyl, guanidino, carbohydrate, and amino.

Candidate compounds matching the above-described general formulae can be retrieved from chemical databases and/or synthesized using methodologies of combinatorial chemistry, well known in the art.

Representative examples of compounds of the present invention are presented in Tables 1-5 that follows.

BTB 14370 Chemistry 0 NH2

BTB 14370-2 Chemistry 2 NH2

BTB 14370-3 Chemistry 4 NH2

BTB 14370-4 Chemistry 6 NH2

BTB 14370-5 Chemistry 8 NH2

BTB 14370-6 Chemistry 10 NH2

BTB 14370-7 Chemistry 12 NH2

BTB 14370-8 Chemistry 14 NH2

BTB 14370-9 Chemistry 16 NH2

BTB 14370-10 Chemistry 18 NH2

BTB 14370-11 Chemistry 20 NH2

BTB 14370-12 Chemistry 22 NH2

BTB 14370-13 Chemistry 24 NH2

BTB 14370-14 Chemistry 26 NH2

BTB 14370-15 Chemistry 28 NH2

BTB 14370-16 Chemistry 30 NH2

BTB 14370-17 Chemistry 32 NH2

BTB 14370-18 Chemistry 34 NH2

BTB 14370-19 Chemistry 36 NH2

BTB 14370-20 Chemistry 38 NH2

BTB 14370-21 Chemistry 40 NH2

BTB 14370-22 Chemistry 42 NH2

BTB 14370-23 Chemistry 44 NH2

BTB 14370-24 Chemistry 46 NH2

BTB 14370-25 Chemistry 48 NH2

BTB 14370-26 Chemistry 50 NH2

BTB 14370-27 Chemistry 52 NH2

BTB 14370-28 Chemistry 54 NH2

RJC 01508 85.534591

NRB 04541 81.132075

NRB 04541-2 81.132075

XBX 00089 65.868263

XBX 00089-2 65.868263

NRB 05186 64.516129

RJC 00044 62.893082

RJC 00044-2 62.893082

RJC 00044-3 62.893082

RJC 00044-4 62.893082

RJC 00044-5 62.893082

RJC 00044-6 62.893082

NRB 05167 48.051948 Table 2

2-Amino-3,4,5,6-tetrahydroxy-hexana]

2-Amino-3,4,5,6-tetrahydroxy-hexanal

2-Amino-3,4,5,6-tetrahydroxy-hexanal

1-Amino-3,4,5,6-tetrahydroxy-hexan-2-one

1 ,3,4,5,6-Pentahydroxy-hexan-2-one

5-Amino-hexane-1 ,2,3,4,6-pentaoI

5-Amino-hexane-1 ,2,3,4,6-pentaol

2,3,4,5-Tetrahydroxy-pentanoic acid hydroxyamide

Hexane-1 ,2,3,4,5,6-hexaol

Hexane-1 ,2,3,4,5,6-hexaol

Hexane-1 ,2,3,4,5,6-hexaol

Hexane-1 ,2,3,4,5,6-hexaol

Hexane-1 ,2,3,4,5,6-hexaol

Hexane-1 ,2,3,4,5,6-hexaol

Hexane-1 ,2,3,4,5,6-hexaol

Hexane-1 ,2,3,4,5,6-hexaol

Hexane-1 ,2,3,4,5,6-hexaol

Hexane-1 ,2,3,4,5,6-hexaol

1 ,6-Dibromo-hexane-2,3,4,5-tetraol

2,3,4,5,6-Pentahydroxy-hexanoic acid amide

2,3,4,5,6-Pentahydroxy-hexanoic acid amide

2-Amino-3,4,5,6-tetrahydroxy-hexanoic acid

1 ,3,4,6-Tetrahydroxy-hexane-2,5-dione

2,3,4,5,6-Pentahydroxy-hexanal oxi e

2,3,4,5,6-Pentahydroxy-hexanal oxime

2,3,4,5,6-Pentahydroxy-hexanal oxime

Hexane-1 ,2,3,4,5-pentaol

6-Methylamino-hexane-1 ,2,3,4,5-pentaol

2,3,4, 5-Tetrahydroxy-pentanoic acid methyl ester

1 -deoxy-1 -(1 -methyl-2-oxohydrazino)pentitol

2,3,4,5,6-Pentahydroxy-hexanoic acid hydrazide

2,3,4,5,6-Pentahydroxy-hexanoic acid hydrazide

1 ,3,4,5,6,7-Hexahydroxy-heptan-2-one

2,3-dihydroxysuccinohydrazide

2,3-dihydroxysuccinohydrazide

Heptane-1 ,2,3,4,5,6-hexaol

Pentane-1 ,2,3,4,5-pentaol

2,3,4,5-Tetrahydroxy-pentanal

2, 3,4,5, 6-Pentahydroxy-hexanoic acid hydroxyamide

2-Hydroxy-N-(2-hydroxy-1 -hydroxymethyl-1 -methyl- ethyl)-propionamide

2,3,4, 5,6,7-Hexahydroxy-heptanal

6-Ethylsulfanyl-hexane-1 ,2,3,4,5-pentaol

Heptane-1 ,2,3,4,5,6,7-heptaol

Heptane-1 ,2,3,4,5,6,7-heptaol

Heptane-1 ,2,3,4,5,6,7-heptaol

Heptane-1 ,2,3,4,5,6,7-heptaol

N-(2,3,4,5,6-Pentahydroxy-hexyl)-acetamide

(2-Amino-3-me.hyl-butyrylamino)-acetic acid

(2-Amino-3-methyl-butyrylamino)-acetic acid

6-Aminomethyl-tetrahydro-pyran-2,3,4,5-tetraol

3-Amino-6-hydroxymethyl-tetrahydro-pyran-2,4,5- triol

2,4-Dihydroxy-N-(2-hydroxy-ethyl)-3,3-dimethyl- butyramide

2,3,4, 5,6, 7-Hexahydroxy-heptanoic acid amide

2-(2-Amino-3-methyl-butyrylamino)-3-hydroxy- propionic acid

ihydroxy-dihydro-furan-

ihydroxy-dihydro-furan-

hydroxy-dihydro-furan-

6-Hydroxymethyl-tetrahydro-pyran-2,3,4,5-tetraol

ethyl-tetrahydro-pyran-

6-Hydroxymethyl-tetrahydro-pyran-2,3,4,5-tetraol

6-Hydroxymethyl-tetrahydro-pyran-2,3,4,5-tetraol

6-Hydroxymethyl-tetrahydro-thiopyran-2,3,4,5- tetraol

6-Hydroxymethyl-tetrahydro-pyran-2,3,4,5-tetraol

6-Hydroxymethyl-tetrahydro-pyran-2,3,4,5-tetraol

6-lodomethyl-tetrahydro-pyran-2,3,4,5-tetraol

6-Fluoromethyl-tetrahydro-pyran-2,3,4,5-tetraol

2,4-Diamino-3,3-dimethyl-pentanedioic acid

(2-Amino-4-methyl-pentanoylamino)-acetic acid

72

2,3,4,5,6,7-Hexahydroxy-heptanoic acid

2,3,4,5,6, 7-Hexahydroxy-heptanoic acid

2,4-Dihydroxy-3,3-dimethyl-butyric acid hydrazide

5-Hydroxymethyl-cyclohexane-1,2,3,4-tetraol

2,4-Dihydroxy-N-(3-hydroxy-propyl)-3,3-dimethyl- butyramide

2,3,4, 5,6-Pentahydroxy-hexanoic acid (2-hydroxy- ethyl)-amide

6,6-Bis-methylsulfanyl-hexane-1 ,2,3,4,5-pentaol

2-Hydroxymethyl-tetrahydro-pyran-2,3,4,5-tetraol

3,6-Bis-hydroxymethyl-[1 ,4]dioxane-2,5-diol

2-hydroxy-2-isopropylmalonohydra∑ide

3,4-Dihydroxy-5-(1 ,2,3-trihydroxy-propyl)-dihydro- furan-2-one

3,4-Dihydroxy-5-(1 ,2,3-trihydroxy-propyl)-dihydro- furan-2-one

3,4-Dihydroxy-5-(1 ,2,3-trihydroxy-propyl)-dihydro- furan-2-one

1 ,3,4,5-Tetrahydroxy-cyclohexanecarboxylic acid

1 ,3,4,5-Tetrahydroxy-cyclohexanecarboxylic acid

2-Acetylamino-3-mercapto-3-methyl-pentanoic acid

2-Amino-4-ethylcarbamoyl-butyric acid

2-Acetylamino-3-mercapto-3-methyl-butyric acid

2-Acetylamino-3-mercapto-3-methyl-butyric acid

2-(1-Carbamoyl-ethoxy)-propionamide

4-Amino-2-hydroxymethyl-6-methoxy-tetrahydro- pyran-3,5-diol

oxy-tetrahydro-furan-

1-[1 ,3]Dithiolan-2-yl-butane-1 ,2,3,4-tetraol

2-hydroxysuccinohydrazide

6-Methyl-tetrahydro-pyran-2,3,4,5-tetraol

6- ethyl-tetrahydro-pyran-2,3,4,5-tetraol

H-O- «fe

Λ

H-N N-((hydroxyamino)carbonyl)pentofuranosylamine

H-N 6-(1 ,2-Dihydroxy-ethyl)-tetrahydro-pyran-2, 3,4,5- tetraol

6-(1 ,2-Dihydroxy-ethyl)-tetrahydro-pyran-2,3,4,5- tetraol

2-EthylsuIfanyl-6-hydroxymethyl-tetrahydro-pyran- 3,4,5-triol

4-Amino-2-hydroxymethyl-5-mercapto-6-methoxy- tetrahydro-pyran-3-ol

2-Hydroxymethyl-6-methoxy-tetrahydro-pyran-3,4,5- triol

2-Hydroxymethyl-6-methoxy-tetrahydro-pyran-3,4,5- triol

2-Hydroxymethyl-6-methoxy-tetrahydro-pyran-3,4,5- triol

2-Formylamino-3-mercapto-3-methyl-butyric acid

N-(2-Carbamoyl-ethyl)-2,4-dihydroxy-3,3-dimethyl~ butyramide

2-Methoxy-6-methyl-tetrahydro-pyran-3,4,5-triol

2-Hydroxy-2-(1 -hydroxy-ethyl)-3-methyl-butyric acid

N-(2,4,5-Trihydroxy-6-hydroxymethyl-tetrahydro- pyran-3-yl)-formamide

N-[5-(1 ,2-Dihydroxy-ethyl)-4-hydroxy-2-oxo- tetrahydro-furan-3-yl]-acetamide

N-[5-(1 ,2-Dihydroxy-ethyl)-4-hydroxy-2-oxo- tetrahydro-furan-3-yl]-acetamide

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-3-methyl-urea

4-Hydroxymethyl-7-methyl-[1 ,3]dioxepane-5,6-diol

4-Hydroxymethyl-7-methyl-[1 ,3]dioxepane-5,6-diol

1-[5-(1 ,2-Dihydroxy-ethyl)-2,2-dimethyl- [1 ,3]dioxolan-4-yl]-ethane-1 ,2-diol

2-Amino-4-(2-chloro-ethylsulfamoyl)-butyric acid

6,6-Bis-ethylsulfanyl-hexane-1 ,2,3,4,5-pentaol

6-[(2-Chloro-ethylamiπo)-methyl]-tetrahydro-pyran- 2,3,4,5-tetrao)

ido)-propyl]-3-methyl-

1-[1 ,3]Dithiolan-2-yl-pentane-1 ,2,3,4,5-pentaol

1 -[1 ,3]Dithiolan-2-yl-pentane-1 ,2,3,4,5-pentaoI

5-Amino-5-[1 ,3]dithiolan-2-yl-pentane-1 ,2,3,4-tetraol

1 -[1 ,3]Dithiolan-2-yl-pentane-1 ,2,3,4,5-pentaoi

6-Methyl-tetrahydro-pyran-2,4,5-triol

6-Methyl-tetrahydro-pyran-2,4,5-triol

2-Amino-6-(2-amino-acetylamino)-hexanoic acid

Acetic acid 3,4,5-trihydroxy-6-methyl-tetrahydro- pyran-2-yl ester

2-(1,2-Dihydroxy-ethyl)-6-methoxy-tetrahydro-pyran- 3,4,5-triol .

1 -[6-(1 ,2-Dihydroxy-ethyl)-5-hydroxy-[1 ,3]dioxan-4- yl]-ethane-1 ,2-diol

2-(1 ,2-Dihydroxy-ethyl)-6-methoxy-tetrahydro-pyran- 3,4,5-triol

2-(1 ,2-Dihydroxy-ethyl)-6-methoxy-tetrahydro-pyran- 3,4,5-triol

3-Hydroxy-N-(3-hydroxy-2,2-dimethyl-propyl)-2,2- dimethyl-propionamide

5-Acetylamino-4-oxo-hex-5-enoic acid amide

1-S-(dimethylarsino)-1-thiohexopyranose

3,4-Dihydroxy-5-(1 ,2,3,4-tetrahydroxy-butyl)- dihydro-furan-2-one

3,4-Dihydroxy-5-(1 ,2,3,4-tetrahydroxy-butyl)- dihydro-furan-2-one

2-Amino-4-butylcarbamoyl-butyric acid

(3-Hydroxy-4-hydroxymethyl-cyclopentyl)-carbamic acid methyl ester

2-(2,4-Dihydroxy-3,3-dimethyl-butyrylamino)- ethanesulfonic acid

2-methylenesuccinohydrazide

2-[Bis-(2-hydroxy-ethyl)-amino]-2-hydroxymethyl- propane-1 ,3-diol

2-Amino-3-hydroxy-3-thiophen-2-yl-propionic acid

ylene-tetrahydro-pyran-

3-Hydroxy-2-hydroxymethyl-2-methyl-propionic acid

2-Amino-3-mercapto-3-methyl-butyric acid methyl ester

2-Amino-N-(2,4,5-trihydroxy-6-hydroxymethyl- tetrahydro-pyran-3-yl)-propionamide

2-(3-Acetylamino-propionylamino)-3-mercapto- propionic acid ethyl ester

6-(1 ,2,3-Trihydroxy-propyl)-tetrahydro-pyran-2,3,4,5- tetraol

6-(1 ,2,3-Trihydroxy-propyl)-tetrahydro-pyran-2,3,4,5- tetraol

2-Methyl-1-oxa-spiro[2.5]octane-4,5,6,7,8-pentaol

2,2,5,5-Tetrakis-hydroxymethyl-cyclopentanone

4-(2-Amino-1 -hydroxy-ethyl)-benzene-1 ,2-diol

4-(1 ,2-Dihydroxy-ethyl)-benzene- ,2-diol

4-(2-Amino-1 -hydroxy-ethyl)-benzene-1 ,2-diol

N-(3,6-Dihydroxy-2-methyl-tetrahydro-pyran-4-yl)- 2,2,2-trifluoro-acetamide

(1 ,2,2-Tris-hydroxymethyl-cyclobutyl)-methanol

2-[2-Amino-3-(1 H-imidazol-4-yl)-propionylamino]-3- hydroxy-propionic acid

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-1 ,3-dihydro-imidazole-2-thione

2,2,6,6-Tetrakis-hydroxymethyl-cyclohexanol

2-Amino-3-mercapto-butyric acid

2-Amino-3-mercapto-butyric acid

2-Methoxy-6-(1 ,2,3-trihydroxy-propyl)-tetrahydro- pyran-3,4,5-tri.ol

2-Hydroxymethyl-5-(2-imino-2,3-dihydro-thiazol-5- yl)-tetrahydro-furan-3,4-diol

4-amino-2-hydroxyphenylarsonic acid

2,4-dihydroxyphenylarsonic acid

2,4-dihydroxyphenylarsonic acid

3-Carbamimidoylsulfanyl-2-methyl-propionamide

2,2,6, 6-Tetrakis-hydroxymethyl-cyclohexanone

2-(2,3-Dihydroxy-propoxy)-benzamide

2-Hydroxymethyl-5-(3-imino-2,3-dihydro- [1 ,2,4]triazol-1 -yl)-tetrahydro-furan-3,4-dioi

Palladium, bis(L-serinato-N,01)-, (SP-4-2)-

1-(2,4-Dihydroxy-6-methyl-pyridin-3-yl)-1-hydroxy- propan-2-one

[1-(Carbamoylmethyl-carbamoyl)-3-methyl-butyl]- carbamic acid allyl ester

3-(3,4-Dihydroxy-5-iodomethyl-tetrahydro-furan-2- yl)-pyrrole-2,5-dione

2-[(2-Hydroxy-ben∑ylidene)-amino]-2-methyl- propane-1 ,3-diol

3,6-Dihydroxy-phthalic acid

N-{[3-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro- furan-2-yl)-ureido]-imino-methyl}-formamide

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-tetrahydro-pyrimidin-2-one

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-1H-pyrimidin-2-one

2,6-Dihydroxy-pyrimidine-4-carboxylic acid bis-(2- hydroxy-ethyl)-amide

2-[(Cyano-hydroxymethyl-methyl-methyl)-azo]-3- hydroxy-2-methyl-propionitrile

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-4-hydroxy-tetrahydro-pyrimidin-2-one

4-Amino-1-(3,4-dihydroxy-5-hydroxymethyl- tetrahydro-furan-2-yl)-1 H-pyridin-2-one (3- deazacytidine)

5-(2-Hydroxy-ethylsulfanylmethyl)-4-hydroxymethyl- 2-methyl-pyridin-3-ol

thyl-tetrahyd ro-pyran-4-

3-Hydrazino-3-(2-hydroxy-phenyl)-propionic acid hydrazide

(6-Ureido-hexyl)-urea

2-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-thiazole-4-carboxylic acid amide

2-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-thlazole-4-carboxylic acid amide

2,3,4, 5-Tetrahydroxy-pentanoic acid N'-benzyl- hydrazide

3-Hydrazino-3-(2-hydroxy-4-methyl-phenyl)- propionic acid hydrazide

Hydroxy-(2-hydroxy-phenyl)-methanesulfonic acid

2-(4-Hyd roxy-5-hyd roxym ethyl-tetrahyd ro-f u ran-2- yl)-5-imino-4,5-dihydro-2H-[1 ,2,4]triazin-3-one

2-Hydroxymethyl-6-imidazol-1-yl-tetrahydro-pyran- 3,4,5-triol

1-(3,4-Dlhydroxy-5-hyclroxymethyl-tetrahydro-furan-

2-yl)-4-imino-3,4-dihydro-l H-pyrlmidln-2-one

(Cytidine)

1-(3,4-Dihydroxy-5-hydroxymethyI-tetrahydro-furan-

2-yl)-4-imino-3,4-dihydro-1 H-pyrimidin-2-one (Aza- cytidine hydrochloride)

6-Amino-3-(3,4-dihydroxy-5-hydroxymethyl- tetrahydro-furan-2-yl)-3H-pyrimidin-4-one

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-4-imino-3,4-dihydro-1 H-pyrimidin-2-one

2-(2-Amino-4-hydroxy-pyrimidin-5-yl)-5- hydroxymethyl-tetrahydro-furan-3,4-diol

(p8eudoisocytidine)

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan-

2-yl)-4-imino-3,4-dihydro-1 H-pyrirnidin-2-one

(Arabinocytidine)

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-3-hydroxy-1 H-pyridin-2-one

3-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-1 H-pyrimidine-2,4-dione

1-(3,4-Dihydroxy-5-hydroxymethyI-tetrahydro-furan- 2-yl)-3-hydroxy-1 H-pyridin-2-one

an-

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-4-thioxo-3,4-dihydro-1 H-pyrimidin-2-one

1-(4-Hydroxy-5-hydroxymethyl-tetrahydro-furan-2- yl)-4-imino-3,4-dihydro-1 H-pyrimidin-2-one (2' deoxy-cytidine, mono hydrochloride)

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-1H-[1,2,3]triazole-4-carboxylic acid amide

2-[Bis-(2-hydroxy-ethyl)-amino]-3-phenyl- propionamide

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan-

2-yl)-3-imino-2,3-dihydro-1 H-pyrazole-4-carboxylic acid amide

2,2-dihydroxy-N'-(2- hydroxybenzylidene)hydrazinecarboximidohydrazide

1-(2,3-Dihydroxy-4-hydroxymethyl-cyclopentyl)-4- imino-3,4-dihydro-1 H-pyrimidin-2-one

2-(3,4-Dihydroxy-5-hydroxymethyI-tetrahydro-furan- 2-yl)-5-hydroxy-2H-pyridazin-3-one

2-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan-

2-yl)-5-imino-4,5-dihydro-2H-[1 ,2,4]triazin-3-one (6- azacytidine)

5-Acetylamino-2-hydroxy-benzoic acid

5-Amino-1-(3,4-dihydroxy-5-hydroxymethyl- tetrahydro-furan-2-yl)-1 H-pyrimidine-2,4-dione

5-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-pyrimidine-2,4-diol

1-(5-Chioromethyl-3,4-dihydroxy-tetrahydro-furan-2- yl)-4-imino-3,4-dihydro-1H-pyrimidin-2-one

Yr 1-(3-Bromo-4-hydroxy-5-hydroxymethyl-tetrahydro- furan-2-yl)-4-imino-3,4-dihydro-1 H-pyrimidin-2-one

1-(5-Fluoromethyl-3,4-dihydroxy-tetrahydro-furan-2- yl)-4-imino-3,4-dihydro-1 H-pyrimidin-2-one

1-(3-Fluoro-4-hydroxy-5-hydroxymethyl-tetrahydro- furan-2-yl)-4-imino-3,4-dihydro-1 H-pyrimidin-2-one

(2'-deoxy-2'-fiuoro-cytidine)

N,N-Bis-(2-hydroxy-ethyl)-4-methyl- benzenesulfonamide

5-Amino-3-(3,4-dihydroxy-5-hydroxymethyl- tetrahydro-furan-2-yl)-3H-imidazole-4-carboxylic acid amide

Cytosine, 1-.beta.-D-arabinofuranosyl-, 3-oxide

3-[Bis-(2-hydroxy-ethyl)-sulfamoyl]-benzoic acid

3-hydroxy-2-pyridinecarbaldehyde thiosemicarbazone

4-Chloro-N,N-bis-(2-hydroxy-ethyl)- benzenesulfonamide

3-Amino-N,N-bis-(2-hydroxy-ethyl)- benzenesulfonamide

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan-

2-yl)-4-imino-6-methyl-3,4-dihydro-l H-pyrimidin-2- one (6-methyl-cytidine)

5-Amino-1-(3,4-dihydroxy-5-hydroxymethyl- tetrahydro-furan-2-yl)-1 H-pyrazole-4-carboxamidine

trahydro-furan- H-pyrimidin-2-

(2,4-Dihydroxy-pyrimidin-5-yl)-carbamic acid ethyl ester

5-Amino-3-(3,4-dihydroxy-5-hydroxymethyl- tetrahydro-furan-2-yl)-3H-imidazole-4-carbonitrile

1-(4,5-Dihydroxy-3-hydroxymethyl-cyclopent-2- enyl)-4-imino-3,4-dihydro-1 H-pyrimidin-2-one

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-5-hydroxy-1 H-pyrimidine-2,4-dione

5-Amino-1-(3,4,5-trihydroxy-tetrahydro-pyran-2-yl)- 1 H-imidazole-4-carboxylic acid amide

4-Amino-2-(3,4-dihydroxy-5-hydroxymethyl- tetrahydro-furan-2-yl)-2H-pyrazole-3-carboxyiic acid amide

5-Amino-1-(3,4,5-trihydroxy-tetrahydro-pyran-2-yl)- 1H-imidazole-4-carboxylic acid amide

ran- -2-

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan-

2-yl)-4-imino-[1 ,3,5]triazinan-2-one (5,6-Dihydro-5- aza-cytidine hydrochloride)

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan-

2-yl)-4-imino-[1 ,3,5]triazinan-2-one (5,6-Dihydro-5- aza-cytidine)

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-4-imino-[1 ,3,5]triazinan-2-one

1-(4,5-Dihydroxy-6-hydroxymethyl-tetrahydro-pyran- 2-yl)-4-imino-3,4-dihydro-1 H-pyrimidin-2-one

6-Chloro-2-(3,4-dihydroxy-5-hydroxymethyl- tetrahydro-furan-2-yl)-5-hydroxy-2H-pyridazin-3-one

1-(4-Amino-5-hydroxymethyl-tetrahydro-furan-2-yl)-

4-imino-3,4-dihydro-1 H-pyrimidin-2-one (3'-amino-

2',3'-dideoxy-cytidine)

2-(4-Hydroxy-5-hydroxymethyl-tetrahydro-furan-2- yl)-6-methyl-2H-[1 ,2,4]triazine-3,5-dione

2-(2,4-Dihydroxy-phenyl)-5-hydroxymethyl- tetrahydro-furan-3,4-diol

5-Amino-1-(3,4-dihydroxy-5-hydroxymethyl- tetrahydro-furan-2-yl)-1 H-[1 ,2,3]triazole-4- carboxamidine

1-(4-Hydroxy-5-hydroxymethyl-3-methoxy- tetrahydro-furan-2-yl)-4-imino-3,4-dihydro-1H- pyrimidin-2-one

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-4-methyiamino-1 H-pyrimidin-2-one

etrahydro- -pyrimidin-

Ureidomethylsulfanylmethyl-urea

Thiocarbamic acid S-[(2-hydroxy-phenylcarbamoyl)- m ethyl] ester

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan-

2-yl)-6-oxo-1 ,6-dihydro-pyridine-3-carboxylic acid amide

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan-

2-yl)-4-imino-3,4-dihydro-1 H-[1 ,3,5]triazin-2-one

(azacytidine)

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-4-imino-3,4-dihydro-1 H-[1 ,3,5]triazin-2-one

1-(5-Chloromethyl-3,4-dihydroxy-tetrahydro-furan-2- yl)-4-imino-[1 ,3,5]triazinan-2-one

5-Hydroxymethyl-2-piperidin-1-ylmethyl-tetrahydro- furan-2,3,4-triol

Dithiocarbamic acid 2,4-dihydroxy-pyrimidin-5- ylmethyl ester

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-4-hydroxyamino-1 H-pyrimidin-2-one

6-Amino-3-(4-hydroxy-5-hydroxymethyl-tetrahydro- furan-2-yl)-3H-pyrimidin-4-one

3-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-6-imino-[1 ,3,5]triazinane-2,4-dione

1-(5-Hydroxymethyl-tetrahydro-furan-2-yl)-4-imino-

3,4-dihydro-1 H-pyrimidin-2-one (2',3'- dideoxycytidine)

2-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-5-hydroxyamino-2H-[1 ,2,4]triazin-3-one

1-(3-Amino-4,5-dihydroxy-6-hydroxymethyl- tetrahydro-pyran-2-yl)-4-imino-3,4-dihydro-1 H- pyrimidin-2-one

1-(4-Hydroxy-5-hydroxymethyl-tetrahydro-furan-2- yl)-4-imino-3,4-dihydro-1 H-[1 ,3,5]triazin-2-one (5- aza-2'-deoxycytidine)

1-(4-Hydroxy-5-hydroxymethyl-tetrahydro-furan-2- yl)-4-imino-3,4-dihydro-1 H-[1 ,3,5]triazin-2-one

2-(2-Amino-4,5-dimethyl-phenylamino)-5- hydroxymethyl-tetrahydro-furan-3,4-diol

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan-

2-yl)-5-hydroxymethyl-1 H-[1 ,2,3]triazole-4-carboxylic acid amide

rahydro-furan- H-pyrimidin-2-

roxymethyl- H-pyrimidin-2-

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-5-fluoro-4-hydroxyamino-1 H-pyrimidin-2-one

3,5-Dihydrazino-[1 ,2,4]triazine-6-carboxylic acid hydrazide

2-(2-Amino-phenoxy)-6-hydroxymethyl-tetrahydro- pyran-3,4,5-triol

2-(4-Chloro-phenylamino)-6-hydroxymethyl- tetrahydro-pyran-3,4,5-triol

2-(4-Bromo-phenyIamino)-6-hydroxymethyl- tetrahydro-pyran-3,4,5-triol

2-Hydroxymethyl-6-phenylamino-tetrahydro-pyran- 3,4,5-triol

2-Hydroxymethyl-6-p-tolylamino-tetrahydro-pyran- 3,4,5-triol

5-Bromo-5-fluoro-1-(4-hydroxy-5-hydroxymethyl- tetrahydro-furan-2-yl)-6-methoxy-dihydro-pyrimidine-

2,4-dione

Propionic acid 3,4-dihydroxy-5-(4-hydroxy-2-oxo- 2H-pyridin-1-yl)-tetrahydro-furan-2-ylmethyl ester

127

1-[4-Hydroxy-2-hydroxymethyl-5-(4-imino-2-oxo-3,4- dihydro-2H-pyrimidin-1-yl)-tetrahydro-furan-3-yl]-3- methyl-urea

2-(2,4-Diamino-6-hydroxy-pyrimidin-5-yloxy)-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Phosphoric acid mono-[4-hydroxy-2-hydroxymethyl-

5-(4-imino-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl)- tetrahydro-furan-3-yl] ester (3'-monophosphate azacytidine)

Phosphoric acid mono-[3,4-dihydroxy-5-(4-imino-2- oxo-3,4-dihydro-2H-pyrimidin-1-yl)-tetrahydro-furan-

2-ylmethyl] ester

Bis-(2,4-dihydroxy-phenyl)-methanone

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-1 ,9-dihydro-purin-2-one

2-[(1 H-Benzoimidazol-2-ylmethyl)-(2-hydroxy-ethyl)- aminoj-ethanol

6-Amino-9-(3,4-dihydroxy-5-hydroxymethyl- tetrahydro-furan-2-yl)-7,9-dihydro-purin-8-one

2-(6-Amino-2-hydroxy-purin-9-yl)-5-hydroxymethyl- tetrahydro-furan-3,4-dioI

2-(2-Amino-6-hydroxy-purin-7-yl)-5-hydroxymethyl- tetrahydro-furan-3,4-diol

-tetrahydro-furan- o[2,3-d]pyrimidin-

2-Hydroxymethyl-5-(4-hydroxy-pyrazolo[3,4- d]pyrimidin-1-yl)-tetrahydro-furan-3,4-diol

2-(4-Amino-pyrazolo[3,4-b]pyridin-1-yl)-5- hydroxymethyl-tetrahydro-furan-3,4-diol

2-(6-Amino-8-imino-7,8-dihydro-purin-9-yl)-5- hydroxymethyl-tetrahydro-furan-3,4-diol

6-Amino-9-(3,4-dihydroxy-5-hydroxymethyl- tetrahydro-furan-2-yl)-7,9-dihydro-purine-8-thione

6-Amino-9-(3,4-dihydroxy-5-hydroxymethyI- tetrahydro-furan-2-yl)-7,9-dihydro-purine-8-thione

2-(6-Hydroxy-8-imino-7,8-dihydro-purin-9-yl)-5- hydroxymethyl-tetrahydro-furan-3,4-diol

9-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-6-hydroxy-7,9-dihydro-purine-8-thione

4-(3,4-Dihydroxy-5-hydroxymethyI-tetrahydro-furan-

2-yI)-7-imino-6,7-dihydro-4H-thiazolo[5,4- d]pyrimidin-5-one

3-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-6-imino-1 ,3,6,7-tetrahydro-purin-2-one

4-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-4H-thiazolo[5,4-d]pyrimidine-5,7-dione

2-Amino-9-(3,4-dihydroxy-5-hydroxymethyl- tetrahydro-furan-2-yl)-6-hydroxy-7,9-dihydro-purine-

8-thione

2-(2-Amino-6-hydroxy-8-imino-7,8-dihydro-purin-9- yI)-5-hydroxymethyl-tetrahydro-furan-3,4-diol

hydroxymethyl- 7,9-dihydro-purin-8-

2-Hydroxymethyl-5-(7-hydroxy-[1 ,2,3]triazolo[4,5- d]pyrimidin-3-yl)-tetrahydro-furan-3,4-diol

2-(4-Hydroxy-imidazo[4,5-d][1 ,2,3]triazin-7-yl)-5- hydroxymethyl-tetrahydro-furan-3,4-diol

2-(4-Amino-[1 ,2,3]triazolo[4,5-c]pyridin-1-yl)-5- hydroxymethyI-tetrahydro-furan-3,4-diol

2-(2-Amino-6-hydroxy-purin-9-yl)-tetrahydro-pyran- 3,4,5-trioI

3-Hyd roxy-1 -(2-hyd roxy-p henyl )-3-pyrid i n-4-yl- propan-1 -one

2-Hydroxymethyl-5-(4-hydroxy-pyrazolo[3,4- d][1 ,2,3]triazin-7-yl)-tetrahydro-furan-3,4-diol

9-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-9H-purine-2,6-diol

2-(2-Hydroxy-6-mercapto-purin-9-yl)-5- hydroxymethyl-tetrahydro-furan-3,4-diol

2-(7-Hydroxy-[1 ,2,3]triazo!o[4,5-d]pyrirnidin-3-yl)- tetrahydro-pyran-3,4,5-triol

2-(6-Amino-purin-3-yl)-5-hydroxymethyl-tetrahydro- furan-3,4-diol

2-Hydroxymethyl-5-(4-mercapto-pyrazolo[3,4- d]pyrimidin-1-yl)-tetrahydro-furan-3,4-diol

o[3,4- ro-furan-

3-aminophenyl(4-aminophenyl)arsinic acid

2-Amino-9-(3,4-dihydroxy-5-hydroxymethyI- tetrahydro-furan-2-yl)-6-mercapto-7,9-dihydro- purine-8-thione

9-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-8-imino-8,9-dihydro-7H-purine-2,6-diol

3-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-6-imino-8-iodo-1 ,3,6,7-tetrahydro-purin-2-one

2-(7-Amino-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5- hydroxymethyl-tetrahydro-furan-3,4-diol

2-(6-Hydroxy-purin-9-yi)-tetrahydro-pyran-3,4,5-triol

2-(6-Amino-purin-9-yl)-tetrahydro-pyran-3,4,5-triol

2-(6-Amino-purin-9-yl)-tetrahydro-pyran-3,4,5-trioI

2-(6-Amino-purin-9-yl)-tetrahydro-pyran-3,4,5-triol

2-(4-Amino-imidazo[4,5-d][1,2,3]triazin-7-yl)-5- hydroxymethyl-tetrahydro-furan-3,4-diol

2-(7-Amino-[1 ,2,3]triazoIo[4,5-d]pyrimidin-3-yl)-5- hydroxymethyl-tetrahydro-furan-3,4-diol

2-Hydroxymethyl-5-(7-mercapto-[1 ,2,3]triazolo[4,5- d]pyrimidin-3-yl)-tetrahydro-furan-3,4-diol

2-Hydroxymethyl-5-(4-mercapto-[1 ,2,3]triazolo[4,5- c]pyridin-3-yl)-tetrahydro-furan-3,4-diol

2-Hydroxymethyl-5-(2-imino-2,3-dihydro- benzoimidazol-1-yl)-tetrahydro-furan-3,4-diol

3-(3,4-Dihydroxy-5-hydroxymethyI-tetrahydro-furan- 2-yl)-lH-pyrazoIo[4,3-d]pyrimidine-5,7-diol

1-(3,4-Dihydroxy-5-hydroxymethyI-tetrahydro-furan- 2-yl)-1 H-imidazo[4,5-d]pyridazine-4,7-diol

ran- -8-

2-(4-Amino-pyrazolo[3,4-d][1 ,2,3]triazin-7-yl)-5- hydroxymethyl-tetrahydro-furan-3,4-diol

3-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yI)-1 H-pyrazolo[3,4-d]pyridazine-4,7-diol

2-Fluoromethyl-5-(6-hydroxy-purin-9-yI)-tetrahydro- furan-3,4-diol

2-(6-Amino-8-bromo-purin-9-yl)-5-hydroxymethyl- tetrahydro-furan-3,4-diol

8-Bromo-9-(3,4-dihydroxy-5-hydroxymethyl- tetrahydro-furan-2-yl)-9H-purine-2,6-diol

2-(4-Amino-5-hydroxymethyi-pyrrolo[2,3-d]pyrimidin- 7-yl)-5-hydroxymethyl-tetrahydro-furan-3,4-diol

2-(7-Amino-6-oxy-[1 ,2,3]triazo)o[4,5-d]pyrimidin-3- yl)-5-hydroxymethyl-tetrahydro-furan-3,4-diol

2-(6-Amino-purin-9-yl)-2,5-bis-hydroxymethyl- tetrahydro-furan-3,4-diol

2-(6-Amino-purin-9-yl)-tetrahydro-thiopyran-3,4,5- triol

2-(6-Mercapto-purin-9-yl)-tetrahydro-pyran-3,4,5- triol

2-(2-Am i no-6-hyd roxy-pu rin-9-yl )-5-m ethyl- tetrahydro-furan-3,4-diol

2-(8-Hydrazino-6-hydroxy-purin-9-yl)-5- hydroxymethyi-tetrahydro-furan-3,4-diol

3-[3-Hydroxy-4-(3,4,5-trihydroxy-6-hydroxymethyl- tetrahydro-pyran-2-yloxy)-phenyl]-acrylic acid

2-Hydroxymethyl-5-(6-mercapto-purin-9-yI)- tetrahydro-thiophene-3,4-diol

2-(6-Amino-purin-9-yl)-6-hydroxymethyl-tetrahydro- pyran-3,4,5-triol

2-(6-Amino-purin-9-yl)-6-hydroxymethyl-tetrahydro- pyran-3,4,5-triol

2-(6-Amino-purin-9-yl)-6-hydroxymethyl-tetrahydro- pyran-3,4,5-triol

4-Amino-7-(3,4-dihydroxy-5-hydroxymethyl- tetrahydro-furan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5- carbonitrile

2-(7-Amino-[1 ,2,3]triazolo[4,5-d][1 ,2,3]triazin-3-yl)-5- hydroxymethyl-tetrahydro-furan-3,4-diol

2-(6-Amino-purin-9-yl)-6-methyl-tetrahydro-pyran- 3,4,5-triol

2-(6-Amino-purin-9-yl)-6-methyl-tetrahydro-pyran- 3,4,5-triol

2-(6-Hydroxy-purin-9-yl)-6-methyl-tetrahydro-pyran- 3,4,5-triol

hy!-tetrahydro-furan-

yl-tetrahydro-furan-

yl-tetrahydro-furan-

ethyl-tetrahydro-furan-

2-(6-Amino-purin-9-yl)-5-methyIene-tetrahydro- furan-3,4-diol

2-(6-Amino-8-hydrazino-purin-9-yl)-5- hydroxymethyl-tetrahydro-furan-3,4-diol

2-(6-Hydroxy-8-hydroxyamino-purin-9-yl)-5- hydroxymethyl-tetrahydro-furan-3,4-diol

1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan- 2-yl)-4-imino-3,4-dihydro-1 H-quinazolin-2-one

2-(6-Amino-8-hydrazino-purin-9-yl)-5- hydroxymethyl-tetrahydro-furan-3,4-diol

2-(2-Amino-6-mercapto-purin-9-yl)-5-methyl- tetrahydro-furan-3,4-diol

2-(6-Amino-purin-9-yI)-5-hydroxymethyl-4-methyl- tetrahydro-furan-3-ol

2-(2-Amino-6-hydroxy-8-hydroxyamino-purin-9-yl)-5- hydroxymethyl-tetrahydro-furan-3,4-diol

1-(6-HydroxymethyI-2,2-dimethyl-tetrahydro- furo[3,4-d][1 ,3]dioxol-4-yl)-4-imino-3,4-dihydro-1 H-

[ ,3,5]triazin-2-one

H- ran-3,4-

2-(4-Amino-pyrrolo[2,3-d]pyrimidin-7-ylmethoxy)- ethanol

2-(6-Mercapto-puri n-9-yl )-6-m ethyl-tetra hyd ro- pyran-3,4,5-triol

2-(6-Chloro-purin-9-yl)-6-methyl-tetrahydro-pyran- 3,4,5-triol

4-Amino-2-(6-amino-purin-9-yl)-5-methyl-tetrahydro- furan-3-ol

4-Amino-2-(6-amino-purin-9-yl)-5-methyl-tetrahydro- furan-3-ol

4-Amino-5-(6-amino-purin-9-yl)-2-methyl-tetrahydro- furan-3-ol

2-(6-Amino-2-fluoro-purin-9-yl)-5-methyl-tetrahydro- furan-3,4-diol

2-(6-Amino-purin-9-yl)-5-ethylidene-tetrahydro- furan-3,4-diol

2-(6-Amino-purin-9-yl)-5-ethylidene-tetrahydro- furan-3,4-diol

4-Ethylsulfanyl-2-hydroxymethyl-5-(6-mercapto- purin-9-yl)-tetrahydro-furan-3-ol

1 ,2,3]triazolo[4,5- yl-tetrahydro-furan-

Table 3

Chemistry 383 384MAYBRIDGE BTB 12005

Chemistry 384 385MAYBRIDGE JFD 01758

Chemistry 38S 386MAYBRIDGE RJC 00925

Chemistry 386 INTERBIOSCREEN STOCK3S-34178

Chemistry 387 INTERBIOSCREEN STOCK3S-91978

Chemistry 388 38ΘINTERBIOSCREEN STOCK1N-05078

Chemistry 389 ^ INTERBIOSCREEN STOCK1 N-10711

Chemistry 390 391 INTERBIOSCREEN STOCK1N-08465

Chemistry 391 INTERBIOSCREEN STOCK1N-04580

Chemistry 3S2 ^INTERBIOSCREEN STOCK2S-87434

INTERBIOSCREEN STOCK1N-16555

Chemistry 394 395MAYBRIDGE BTB 11983

Chemistry 395 396 AYBRIDGE XBX 00208

Chemistry 396 397 INTERBIOSCREEN STOCK4S-00529

Chemistry 397 INTERBIOSCREEN STOCK1S-07789

Chemistry 398 398 Florida Center of Heterocyclic Compounds 14322

Chemistry 399 .00 Florida Center of Heterocyclic Compounds 14325

Chemistry 400 .01 Florida Center of Heterocyclic Compounds 14380

Chemistry 401 402 Florida Center of Heterocyclic Compounds 14390

Chemisiry 402 403 Florida Center of Heterocyclic Compounds 14392

10 Florida Center of Heterocyclic Compounds 14396

Chemistry 404 405Florida Center of Heterocyclic Compounds 15667

Chemistry 405 06 Florida Center of Heterocyclic Compounds 15683

Chemistry 406 4Q7MAYBRIDGE HTS 09791

Chemistry 407 ' INTERBIOSCREEN STOCK1N-28299

Chemistry 408 INTERBIOSCREEN STOCK1 N-30833

Chemistry 409 410INTERBIOSCREEN STOCK3S-30397

Table 4

[Chemistry β INTERBIOSCREEN STOCK1 S-00389

[Chemistry 7 INTERBIOSCREEN STOCK1S-03829

[Chemistry 8 INTERBIOSCREEN STOCK1 -02042

IChamistry 9 INTERBIOSCREEN STOCK1 N-08175

|Chβmis.r 10 INTERBIOSCREEN STOCK1 N-27724

[Chemistry 11 INTERBIOSCREEN STOCK1N-27823

INTERBIOSCREEN STOCK1 N-28278 IChernistry 12

IChemistry 13 INTERBIOSCREEN STOCK1 S-00337

IChemistry 14 INTERBIOSCREEN BTOCK1S-57625

IChemistry 15 INTERBIOSCREEN STOCK2S-14635

IChemistry 16 INTERBIOSCREEN STOCK2S-14938

IChemistry 17 INTERBIOSCREEN STOCK1 S-02848

IChemistry 18 INTERBIOSCREEN STOCK1 S-06085

IChemistry 19 INTERBIOSCREEN STOCK1S-11457

IChemistry 20 INTERBIOSCREEN STOC 1S-56574

IChemistry 21 INTERBIOSCREEN STOCK3S-61212

IChemistry 22 INTERBIOSCREEN STOCK1 S-00019

IChemistry 23 INTERBIOSCREEN STOCK1 N-01624

IChemistry 24 INTERBIOSCREEN STOCK1 -02648

IChemistry 25 INTERBIOSCREEN STOC 1 -03653

JGhemistry 26 INTERBIOSCREEN STOCK1 -06440

IChemistry 27 INTERBIOSCREEN STOC 1 -06756

IChemistry 28 INTERBIOSCREEN STOCK1 -07036

IChemistry 29 INTERBIOSCREEN STOCK1N-08795

IChemistry 30 INTERBIOSCREEN STOCK1 N-09990

IChemistry 37 INTERBIOSCREEN STOC 1S-04527

[Chemistry 38 INTERBIOSCREEN STOCK1S-09433

IChemistry 39 INTERBIOSCREEN STOCK1S-10645¹

[Chemistry 40 INTERBIOSCREEN STOCK1S-57164

chemistry 41 INTERBIOSCREEN STOCK1S-87515

Chemistry 42 INTERBIOSCREEN STOCK2S-66046

IChemistry 43 INTERBIOSCREEN STOCK2S-66275

IChemistry 44 INTERBIOSCREEN STOCK2S-66491

Chemistry 45 INTERBIOSCREEN STOCK1 S-49568

IChemistry 46 INTERBIOSCREEN STOC 1S-90337

IChemistry 47 INTERBIOSCREEN STOCK2S-62322

IChemistry 48 INTERBIOSCREEN STOCK1 S-08290

IChemistry 49 INTERBIOSCREEN STOCK1 S-14055

IChemistry 50 INTERBIOSCREEN STOCK1S-43706

Chemistry 51 INTERBIOSCREEN STOCK1S-55323

IChemistry 52 INTERBIOSCREEN STOCK2S-92270

[Chemistry 53 INTERBIOSCREEN STOCK3S-04481

IChemistry 61 INTERBIOSCREEN STOCK3S-90800

IChemistry 62 INTERBIOSCREEN STOCK4S-1 572

iGhemislry 63 INTERBIOSCREEN STOCK4S-19290

IChemistry 84 INTERBIOSCREEN STOCK4S-26901

IChemistry 65 INTERBIOSCREEN STOCK4S-30821

IChemistry 66 INTERBIOSCREEN STOCK1S-06060

[Chemistry 67 INTERBIOSCREEN STOCK1S-44720

IChemistry 68 INTERBIOSCREEN STOCK2S-01003

IChemistry 69 INTERBIOSCREEN STOCK2S-91427

IChemistry 70 MAYBRIDGE BTB 08972

IChemistry 71 MAYBRIDGE BTB 11575

IChemistry 72 MAYBRIDGE BTB 11576

[C emistry 86 MAYBRIDGE HTS 11454

Chemistry 87 MAYBRIDGE HTS 11478

[Chemistry 88 MAYBRIDGE JFD 00706

Chemistry 89 MAYBRIDGE JFD 01818

[Chemistry 80 MAYBRIDGE JFD 01819

iChe istry 91 MAYBRIDGE JFD 01824

[Chemistry 92 MAYBRIDGE JFD 01826

[Chemistry 93 MAYBRIDGE JFD 01835

[Chemistry 94 MAYBRIDGE JFD 02792

Chemistry 95 MAYBRIDGE RDR 01531

[Chemistry 96 AYBRIDGE RJC 00436

[Chemistry 97 MAYBRIDGE RJC 02491

[Chemistry 98 MAYBRIDGE RJC 03102

iChemistry 106 MAYBRIDGE BTBS 00022

IChemistry 107 MAYBRIDGE BTBS 00079

IChemistry 108 MAYBRIDGE RJC 03982

IChemistry 109 MAYBRIDGE BTB 14739

IChemistry 110 MAYBRIDGE JFD 01836

IChemistry 111 INTERBIOSCREEN STOCK1N-01103

IChemistry 112 INTERBIOSCREEN STOCK1 N-02683

IChemistry 113 INTERBIOSCREEN STOCK1N-04231

IChemistry 114 INTERBIOSCREEN STOCK1 -07114

IChemistry 115 INTERBIOSCREEN STOCK1 N-06332

IChemistry 116 INTERBIOSCREEN STOCK1 -25941

IChemistry 117 INTERBIOSCREEN STOCK1 -30675

IChemistry 118 INTERBIOSCREEN STOCK1 N-31108

[Chemistry 119 INTERBIOSCREEN STOCK1N-31 68

Chemistry 120 INTERBIOSCREEN STOCK1N-32393

Chemistry 121 INTERBIOSCREEN STOCK1N-32451

Chemistry 122 INTERBIOSCREEN STOC 1N-32471

[Chemistry 1. INTERBIOSCREEN STOCK1N-34498

Chemistry 124 INTERBIOSCREEN STOCK1N-00713

IChemistry 125 INTERBIOSCREEN STOCK1N-02451

[Chemistry 126 INTERBIOSCREEN STOC 1 -08612

IChemistry 127 INTERBIOSCREEN STOCK1N-08959

IChemistry 128 INTERBIOSCREEN STOCK1 -09813

IChemistry 129 INTERBIOSCREEN STOCK1N-09957

[Chemistry 130 INTERBIOSCREEN STOCK1N-11894

IChemistry 131 INTERBIOSCREEN STOCK1 N-16412

IChemistry 132 INTERBIOSCREEN STOCK1N-1 160

IChemistry 133 INTERBIOSCREEN STOCK1N-34396

IChemistry 134 INTERBIOSCREEN STOCK1 -34952

IChemistry 135 INTERBIOSCREEN STOCK1 N-12937

Chemistry 141 INTERBIOSCREEN STOCK1 N-30415

IChemistry 142 INTERBIOSCREEN STOC 1N-31629

IChemistry 143 INTERBIOSCREEN STOC 1 -36065

IChemistry 144 INTERBIOSCREEN STOC 2S-14532

CH

IChemistry 145 INTERBIOSCREEN STOCK2S-29935

/

IChemistry 146 INTERBIOSCREEN STOCK2S-51257 IChemistry 147 INTERBIOSCREEN STOCK2S-97300

IChemistry 148 INTERBIOSCREEN STOCK3S-29452

IChemistry 149 INTERBIOSCREEN STOCK2S-96478

IChemistry 150 INTERBIOSCREEN STOCK3S-53594

IChemistry 151 INTERBIOSCREEN STOCK3S-75413

IChemistry 152 INTERBIOSCREEN STOCK3S-82020

Chemistry 159 INTERBIOSCREEN STOCK1 S-01286

IChemistry 160 INTERBIOSCREEN STOCK1 S-01857

IChemistry 161 INTERBIOSCREEN STOCK1S-02710

IChemistry 162 INTERBIOSCREEN STOCK1S-09722

IChemistry 163 INTERBIOSCREEN STOCK1S-43089

IChemistry 164 INTERBIOSCREEN STOCK1 S-59110

IChemistry 165 INTERBIOSCREEN STOC 2S-00203

IChemistry 166 INTERBIOSCREEN STOCK2S-00204

IChemistry 167 INTERBIOSCREEN STOCK2S-03916

[Chemistry 168 INTERBIOSCREEN STOC 2S-04991

IChemistry 169 INTERBIOSCREEN STOCK2S-06147

IChemistry 170 INTERBIOSCREEN STOC 2S-08071

IChemistry 171 INTERBIOSCREEN STOCK2S-14505

IChemistry 172 INTERBIOSCREEN STOCK2S-37403

IChemistry 173 INTERBIOSCREEN STOCK3S-80719

IChemistry 174 INTERBIOSCREEN STOCK3S-95865

IChemistry 175 INTERBIOSCREEN STOCK4S-26650

IChemistry 176 INTERBIOSCREEN STOCK1 S-10649

IChemistry 177 INTERBIOSCREEN STOC 2S-16711

IChemistry 178 INTERBIOSCREEN STOC 2S-17278

Chemistry 178 INTERBIOSCREEN STOCK1 S-00004

IChemistry 180 INTERBIOSCREEN STOCK1S-02771

IChemistry 181 INTERBIOSCREEN STOCK1 S-06565

IChemistry 182 INTERBIOSCREEN STOCK1S-10442

IChemistry 183 INTERBIOSCREEN STOCK1S-38882

IChemistry 184 INTERBIOSCREEN STOCK1S-39415

IChemistry 185 INTERBIOSCREEN STOCK1 S-40016

IChemistry 188 INTERBIOSCREEN STOCK1S-45382

IChemistry 187 INTERBIOSCREEN STOC 1S-61451

IChemistry 188 INTERBIOSCREEN BTOCK1 S-63395

IChemistry 189 INTERBIOSCREEN STOCK1S-69875

INTERBIOSCREEN STOCK1 S-87779 IChemistry 190

IChemistry 191 INTERBIOSCREEN STOC 1S-88081

IChemistry 192 INTERBIOSCREEN STOCK2S-02591

IChemistry 193 INTERBIOSCREEN STOC 2S-02802

IChemistry 194 INTERBIOSCREEN STOCK2S-03945

IChemistry 195 INTERBIOSCREEN STOCK2S-04520

IChemistry 196 INTERBIOSCREEN STOCK2S-04777

IChemistry 197 INTERBIOSCREEN STOC 2S-05952

IChe istry 198 INTERBIOSCREEN STOC 2S-08997

IChemistry 199 INTERBIOSCREEN STOC 2S-12921

IChemistry 200 INTERBIOSCREEN STOCK2S-14631

NH_j

IChemistry 201 INTERBIOSCREEN STOCK2S-15725

IChemistry 202 INTERBIOSCREEN STOCK2S-15855 IChemistry 203 INTERBIOSCREEN STOCK2S-48284

IChemistry 204 INTERBIOSCREEN STOC 2S-61051

IChemistry 205 INTERBIOSCREEN STOCK1 -30229

IChemistry 206 INTERBIOSCREEN STOCK1N-30279

IChemistry 207 INTERBIOSCREEN STOC 1N-32211

IChemistry 213 INTERBIOSCREEN STOCK1 N-11445

IChemistry 214 INTERBIOSCREEN STOC 1 N-12325

IChemistry 215 INTERBIOSCREEN STOCK1 -16212

IChemistry 216 INTERBIOSCREEN STOC 1 N-18587

IChemistry 217 INTERBIOSCREEN STOCK1 N-21263

[Chemistry 218 INTERBIOSCREEN STOCK1N-28517

Chemistry 219 INTERBIOSCREEN STOCK1N-29779^!

[Chemistry 220 INTERBIOSCREEN STOCK1N-35599

[Chemistry 221 INTERBIOSCREEN STOC 1N-37395

Chemistry 222 INTERBIOSCREEN STOCK1N-37849

H-N' "OH

[Chemistry 223 INTERBIOSCREEN STOCK2S-69939

INTERBIOSCREEN STOCK2S-77962 IChemistry 224

IChemistry 225 INTERBIOSCREEN STOC 2S-81797

IChemistry 226 INTERBIOSCREEN STOCK2S-93796

IChemistry 227 INTERBIOSCREEN STOCK3S-27001

IChemistry 228 INTERBIOSCREEN STOC 3S-35118

Chemistry 229 INTERBIOSCREEN STOCK3S-36813

IChemistry 230 INTERBIOSCREEN STOCK3S-54283

IChemistry 231 INTERBIOSCREEN STOCK3S-55706

IChemistry 232 INTERBIOSCREEN STOC 3S-56240

IChemistry 233 INTERBIOSCREEN STOCK3S-59627

IChemistry 234 INTERBIOSCREEN STOCK3S-60316

IChemistry 235 INTERBIOSCREEN STOCK3S-60428

INTERBIOSCREEN STOCK3S-61948 IChemistry 236

IChemistry 237 INTERBIOSCREEN STOCK3S-69070

IChemistry 238 INTERBIOSCREEN STOC 3S-69363

IChemistry 239 INTERBIOSCREEN STOCK3S-77315

IChemistry 240 INTERBIOSCREEN STOCK3S-88742

IChemistry 241 INTERBIOSCREEN STOCK3S-89508

IChemistry 242 INTERBIOSCREEN STGCK3S-96401

IChemistry 243 INTERBIOSCREEN STOCK4S-08584

IChemistry 244 INTERBIOSCREEN STOCK4S-19445

IChemistry 245 INTERBIOSCREEN STOCK1 -00777

IChemistry 246 INTERBIOSCREEN STOCK1 -02355

IChemistry 247 INTERBIOSCREEN STOCK1 N-03044

[Chemistry 258 MAYBRIDGE HTS 09785

ϊ ernϊst y 2S9 MAYBRIDGE HTS 09788

ts Lir 260 SAYBRIDGE HTS 09789

Chβmisti 26 ι IAYBRIDGE HTS 09796

Chemistrv 262 IAYBRIDGE NTS 11218

IhβT istry 263 SAYBRIDGE KM 09581

Chymi?nv < 5 INTERBIOSCREEN STOCK1S-91339

Chfiinistι 27( INTERBIOSCREEN STOCK1S-95510

ifaiiii , r INTERBIOSCREEN STOCK2S-94073

rh mi?trv 27G INTERBIOSCREEN STOCK3S-00830

Chemιstιv270 INTERBIOSCREEN STOCK3S-51991

Ch9iYitsir 280 INTERBIOSCREEN 3TOCK1N-03303

*e i_ ry 2S1 INTERBIOSCREEN STOCK1N-32808I

Chemistry 2B INTERBIOSCREEN STOC 1S-02305

ϊhem trv 28^'3 INTERBIOSCREEN STOC 1N-00191

Che isty 2SA INTERBIOSCREEN STOC 1N-01596

I ln.'ini ,itv ..*''!' INThKDIOSCREr.N SlOC IN •048!).'

Chemistry "256 INTERBIOSCREEN STOCK1N-05508

Chemistry : INTERBIOSCREEN STOC 1N-06610

.hemistry ?SS INTERBIOSCREEN STOCK1N-07878

ϊ&umisrrv 289 INTERBIOSCREEN [STOCK1N-09237

Chemistry 223 INTERBIOSCREEN STOCK1N-25401

hε istrv 2B6 INTERBIOSCREEN STOCK1N-30629

?hs isf ry 29? INTERBIOSCREEN &TOCK1N-31095

Chemistry 28a INTERBIOSCREEN STOCK"! N-33672I

[Chemistry 259 INTERBIOSCREEN STOCK1N-33692I

Chemistrv 315 INTERBIOSCREEN STOCK1N-34288

Chemistry 31 S INTERBIOSCREEN STOCK1N-34296

^'Chemistry 317 INTERBIOSCREEN STOCK1N-34314

Chemistry 318 TERBIOSCREEN STOCK1N-39078

C cntiεlnf 3 U MAYBRIDGE JFD 00878

Chsmistr* J52 INTERBIOSCREEN STOCK2S-S039S

IChemislr'f 35, INTERBIOSCREEN ISTOCK2S-92713

C "ar ^'s* ry 3β4 INTERBϊOSCREEf STOCK3S-35749

Chemistrv bh INTERBIOSCREEN STOCK3S-36493

Chetnistr* 356 INTERBIOSCREEN JSTOCK3S- 3486

.hsroistr 3o. INTERBIOSCREEN STOCK3S-43615

[Chemistry 358 INTERBIOSCREEN STOCK4S-Q2493

C emistr* INTERBIOSCREEN STOCK1S-92601

,nSs»ni3^« INTERBIOSCREEN STOCK1S-94678

Che m^'εtπ* Iii INTERBIOSCREEN STGCK2S-27413

INTERBIOSCREEN STOC 2S-30426 Chemistry 362

[Charrtisfry 363 INTERBIOSCREEN STOCK2S-62067

IChamistr £6 INTERBIOSCREEN STOCK3S-00546

ΓΛ

|Chem.s-ry 365 INTERBIOSCREEN STOC 3S-30S98

[Chemistry 366 INTERBIOSCREEN STOCK3S-31988

Che i try 367 INTERBIOSCREEN STOCK3S-32690

ICharr-isu? Sg INTERBIOSCREEN STQCrC3S-39S3β'

Chemist r* 369 INTERBIOSCREEN STOC 3S-46883

|Chsmistry 3?0 INTERBIOSCREEN STOCK3S-65202

Chemistry 371 INTERBIOSCREEN STOCK4S-11820

INTERBIOSCREEN STOCK1S-01608

jChemisfr/ 3? I MAYBRIDGE HTS 12149

Chemistry 3? 8 .AYBRIDGE HTS 12151

Chem try 3/8 MAYBRIDGE HTS 12152

Chemistry 38& .AYBRIDGE HTS 12156

Chemistry 3S1 ΪAYBRIDGE KM 10572

Chemistrv 382 flAYBRIPGE [RH 01023

Chomi&trv 007

HO_{^ ^ ^}NH,

' amisiP OSS MAYBRIDGE RJC 00044

rhernbtrt* 009 MAYBRIDGE JFD 00523

Che isr 010 MAYBRIDGE KBX 00317

Chemistry Gil ICN 102S90

OH

^OH

Jhismϊst / 01? MAYBRIDGE LJFD 00282

Ch rnisfτ¥0t3 MAYBRIDGE 'HTS 06535

Table 5

Chemistry 0 5586-3627

Chemistry 2 0273-004

Chemistry ? 1770-0398

Chemistry 4 2582-0068

Chemistry δ 3910-0334

Chemistry 6 4572-0550

Chemistry 7 5586-3825

nsmi 8012-8987

Chemistry 8 8013-1127

Chemistry 10 0723-2090

Chemistry 11 0723-2096

Chemistrv 12 2001-0077

Chemistry 2713-0095

Chemistry 14 3900-0007

Chamtetry 15 4048-2041

Chemistry tβ 8008-3598

Chemistrv 17 8010-5919

Chemistry 18 K402-1024

Chemistry 18 5898-2312

Chemistry 20 K402-0873

Chemistry ;<rl K402-0980

Chemistry 22 3329-3622

Chemistry 23 3010-0435

Chemistry 24 K786-4586

^■hemlstry 25 K788-8840

hemisir/ 26 3993-GS82

Chomistr/ 77 4572-055?

Chem.ε.ry 28 5491-0469

Cnemistry 29 8013-0076

Chemistry 30 2237-1327

Chemistry 31 2713-0022

Chεr islry 32 2713-0096

Chsmistry 33 5339-0155

Chemistry 34 5671-0012

Chemistry 35 5671-0025

Chemistry 36 3021-0034

Chemistry 37 3209-0042

Chemistry 38 3209-0047

Chemistry 39 3209-0048

Chemistry 40 3209-0418

Chemistry 41 3209-0462

Chemistry 42 3209-0655

Chemistry 43 Ϊ209-0899

Chemistry 44 320S-0993

Chemistrv 43 3209-102S

C emistry 4§ 3209-1202

Chemistr 47 6049-2364

Ghemisxr 48 8009-2981

Chemistry 49 2713-0104

Chemistry 50 C143-0102

Chemistry 51 1232-0019

Chemistry 52 1232-0028

Chemistrv 53 1232-0029

Chemistry S4 1355-0038

Chemistry 55 1355-0087

Chemistry 56 1355-0096

Chemistry S7 1682-2554

Chemistry 58 1682-7564

Chemistry 59 2516-2195

Chemistry 80 4491-0204

The fact that most of the compounds uncovered using the methodology of the present invention are nucleotide and nucleotide-like molecules substantiates the accuracy of the presently constructed structural models of apobec-1 and pharmacophoric interactions thereof, since as described hereinabove it is well known that Apobec-1 binds an RNA substrate.

Promising candidate compounds can then be synthesized for further qualification (e.g., determining binding constants etc.). Thus, for example, an Apobec-1 polypeptide sequence which includes the active-site cavity can be bound to a solid support, for example, via biotin-avidin linkage and a candidate compound is allowed to equilibrate therewith to test for binding thereto. Generally, the solid support is washed and compounds that are retained are selected as promising compounds. In order to facilitate visualization, compounds may be labeled, for example, by radiolabeling or with fluorescent markers.

Another highly effective means of testing binding interactions is via surface plasmon resonance analysis, using, for example, commercially available BIAcore chips (Pharmacia). Such chips may be coated with either the Apobec-1, or portion thereof comprising the active site cavity, or with the candidate compound, and changes in surface conductivity are then measured as a function of binding affinity upon exposure of one member of the putative binding pair to the other member of the pair.

Once identified, candidate compounds of the present invention are preferably biologically qualified for Apobec-1 inhibitory activity, by, for example, assaying cytidine deaminase activity, aρoB48 expression and/or secretion or, preferably, fat metabolism.

Qualification of inhibitory activity is preferably effected with respoect to know Apobec-1 inhibitors. For example, a biological sample (tissue or cell-line), which expresses an endogenous or exogenous Apobec-1 protein can be exposed to a candidate compound which exhibits 0.1 % KM, preferably at least 5 % KM, at least 10% K_M, at least 20 % K_M, at least 50 % K_M, at least 100% K_M, at least 120% K_M) at least 140% K_M; at least 160% K_M, at least 180% K_M, at least 200 % K_M> at least 220 % K_M, at least 240 % K_M, at least 260 % K_M, at least 300 % K_M, at least 320 % K_M, at least 340 % K_M> at least 360 % K_M, at least 380 % K_M> at least 400 % K_M, at least 420 % K_M, at least 440 % K_M, at least 460 % K_M, at least 480% K_Mj say at least 500 % K_M as compared to Apobec-1 inhibitors such as those described in Tables 1-5. Assays for determining Apobec-1 activity in the presence of the candidate composition are described infra.

Fat metabolism - Total cholesterol and triglyceride concentrations can be determined enzymatically using commercially available kits (Wako and Sigma, respectively), such as those described in Oka (1997) J. Biol. Chem. 272:1456-1460.

In vitro deamination activity assay - Typically can be carried out as described previously [Teng, B., and Davidson, N. O. (1992) J. Biol. Chem. 267, 21265-21272], using 8 f ol of synthetic substrate in the presence of enterocyte S-100 extracts.

Primer extension products are fractionated on a 6 % polyacrylamide, 8 M urea gel and quantified by exposure to a phosphor screen (Molecular Dynamics).

Alternatively, large scale screening for candidate compounds which have inhibitory effect on the deaminase activity of Apobec-1 can be effected using an anchor apoB RNA template in which deamination takes place, a crude extract of cell proteins which allow deamination, oligonucleotide primers for detecting the deamination of cytidine in the RNA template, modified nucleotides and the candidate compound of interest (see U.S. Pat. No. 6,210,888). It will be appreciated that this methodology is effected using automated machinery to allow large scale validation of compounds which inhibit Apobec-1 activity.

In-vivo plasma lipoprotein and apoB analysis - Mice treated with at least one concentration of the candidate compound of the present invention and for at least one period of time are fasted for 6 hours and blood is collected into tubes containing EDTA. Plasma (0.2 ml) collected from individual mice is fractionated by fast protein liquid chromatography (FPLC) using two Superose 6 columns (Pharmacia Biotech, Inc.) connected in series. Fifty 0.5 ml fractions are collected using the eluent 1 mM EDTA, 154 mM NaCl, and 0.02 % NaN₃ (pH 8.2). Cholesterol and triglyceride contents of each FPLC fraction and of plasma are determined enzymatically as described above.

For analysis of plasma apoB, lipoproteins of diameter smaller than 1.21 prepared by ultracentrifugation from plasma pooled from a number of individual animals are fractionated on 4-15% SDS gel and stained with Coomassie Blue. The apoB-100 and apoB-48 bands are quantified by densitometer measurements. ApoB- 100 and apoB-48 protein level can be determined using other methods which are well known in the art, such as Western blot analysis using antibodies available from, for example, Japan Irnmunoresearch Laboratories.

Compounds which exhibit Apobec-1 inhibitory activity (i.e., preferably at least 20 % inhibition) are tested for cytotoxicity and therapeutic efficacy using clinical procedures which are well known in the art.

The compounds of the present invention can be used to modulate fat metabolism of individuals, which have or are predisposed to conditions or disorders associated directly or indirectly with abnormal fat metabolism. Examples include, but are not limited to, overweight, obesity (i.e., at least 20 % over the average weight for the person's age, sex and height), type II diabetes, hyperglycemia, hyperinsulinemia, eleveated blood levels of fatty acids or glycerol, syndrome X, diabetic complications, dysmetabolic syndrome and related diseases, sexual dysfunction, hypercholesterolemia, atherosclerosis, hypertension, pancreatitis, hypertriglycerideamia, hyperlipidemia, Alzheimer's disease, osteopenia, stroke, dementia, coronary heart diseases, peripheral vascular diseases, peripheral arterial diseases, vascular syndromes, reducing myocardial revascularization procedures, microvascular diseases (e.g., neuropathy, nephropathy and retinopathy), nephritic syndrome, hypo-α-lipoproteinemia, cholesterol-related disorders (e.g., LDL-pattern B and LDL-pattern L), cerebrovascular diseases, malignant lesions (e.g., ductal carcinoma in situ), premalignant lesions, gastrointestinal malignancies (e.g., liposarcoma, epithelial tumors, irritable bowel syndrome, Crohn's disease, gastric ulceritis, gallstones), HIV infections, drug-induced lipodystrophy, inflammatory disorders, eating disorders (e.g., anorexia bulimia), diseases associated with low levels of HDL (e.g., athrosclerotic diseases) and climacteric. It will be appreciated that the compounds of the present invention may also be used to modulate body fat content. Thus, for example, compounds of the present invention can be used to reduce percent body fat as is often desired by athletes.

As used herein the term "treating" refers to preventing, curing, reversing, attenuating, alleviating, minimizing, suppressing or halting the deleterious effects of a condition or disorder associated with abnormal fat metabolism symptoms and/or disease state.

Thus, according to another aspect of the present invention there is provided a method of modulating fat metabolism in a subject in need thereof. As used herein the phrase "subject in need thereof refers to a mammal, preferably a human which can benefit from modulation of fat metabolism using the compounds of the present invention.

The method is effected by administering to the subject a therapeutically effective amount of an Apobec- 1 inhibitor of the present invention.

The compound of the present invention can be provided to the subject er se, or as part of a pharmaceutical composition where it is mixed with a pharmaceutically acceptable carrier.

As used herein a "pharmaceutical composition" refers to a preparation of one or more of the active ingredients described herein with other chemical components such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

Herein the term "active ingredient" refers to the compound preparation, which is accountable for the biological effect.

Hereinafter, the phrases "physiologically acceptable carrier" and

"pharmaceutically acceptable carrier" which may be interchangeably used refer to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. An adjuvant is included under these phrases. One of the ingredients included in the pharmaceutically acceptable carrier can be for example polyethylene glycol (PEG), a biocompatible polymer with a wide range of solubility in both organic and aqueous media (Mutter et al. (1979).

Herein the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient.

Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

Techniques for formulation and administration of drugs may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition, which is incorporated herein by reference.

Suitable routes of administration may, for example, include oral, rectal, transmucosal, especially transnasal, intestinal or parenteral delivery, including intramuscular, subcutaneous and intramedullary injections as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. The preferred route of administration is presently oral.

Pharmaceutical compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which, can be used pharmaceutically.

Proper formulation is dependent upon the route of administration chosen.

For injection, the active ingredients of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestiόn by a patient. Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl- cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical compositions, which can be used orally, include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

For administration by nasal inhalation, the active ingredients for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro- tetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in a dispenser may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The preparations described herein may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative. The compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active ingredients may be prepared as appropriate oily or water based injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes.

Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran.

Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the active ingredients to allow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water based solution, before use.

The preparation of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.

Pharmaceutical compositions suitable for use in context of the present invention include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a therapeutically effective amount means an amount of active ingredients effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.

Determination of a therapeutically effective amount is well within the capability of those skilled in the art.

For any preparation used in the methods of the invention, the therapeutically effective amount or dose can be estimated initially from in vitro assays. For example, a dose can be formulated in animal models (e.g., obese models such as disclosed by Bayli's J Pharmacol Exp Ther. 2003; and models for atherosclerosis such as described by Brousseau J Lipid Res. 1999 40(3):365-75) and such information can be used to more accurately determine useful doses in humans.

Toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, in cell cultures or experimental animals. The data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. [See e.g.,

Fingl, et al., (1975) "The Pharmacological Basis of Therapeutics", Ch. 1 p.l].

Depending on the severity and responsiveness of the condition to be treated, dosing can be effected over a short period of time (i.e., several days to several weeks) or until cure is effected or diminution of the disease state is achieved.

The amount of a composition to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.

Compositions including the preparation of the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

Compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accommodated by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.

It will be appreciated that the Apobec-1 inhibitors of the present invention may be administered in combination with other drugs to achieve enhanced effects. It will be further appreciated that the Apobec-1 inhibitors of the present invention may also be provided as food additives.

The phrase "food additive" [defined by the FDA in 21 C.F.R. 170.3(e)(1)] includes any liquid or solid material intended to be added to a food product. This material can, for example, include an agent having a distinct taste and/or flavor or physiological effect (e.g., vitamins).

The food additive composition of the present invention can be added to a variety of food products . As used herein, the phrase "food product" describes a material consisting essentially of protein, carbohydrate and/or fat, which is used in the body of an organism to sustain growth, repair and vital processes and to furnish energy. Food products may also contain supplementary substances such as minerals, vitamins and condiments. See Merriani-Webster's Collegiate Dictionary, 10th Edition, 1993. The phrase "food product" as used herein further includes a beverage adapted for human or animal consumption.

A food product containing the food additive of the present invention can also include additional additives such as, for example, antioxidants, sweeteners, flavorings, colors, preservatives, enzymes, nutritive additives such as vitamins and minerals, emulsifiers, pH control agents such as acidulants, hydrocolloids, antifoams and release agents, flour improving or strengthening agents, raising or leavening agents, gases and chelating agents, the utility and effects of which are well-known in the art.

Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with the above descriptions, illustrate the invention in a non limiting fashion.

Construction of a 3D model for human APOBEC-1 by homology modeling:

Sequence Alignment: As no structural information regarding Apobec-1 is available, its 3D model was constructed by sequence alignment of Apobec-1 and known proteins. The validity and preciseness of such a modeling depend on the homology of the proteins.

An exemplary known protein is ECCDA - E. Coli cytidine deaminase (GenBank Accession No. PI 3652), of which some data exists. However, the Apobec-1 and ECCDA have homology of less than 30 %, and therefore simple algorithms that allow almost automatic alignment of sequences are inefficient in this case.

This limitation can be circumvented by multiple sequence alignment. Hence, protein databases were Blast [National Center of Biotechnology Information (NCBI)] searched for sequences having close homology to Apobec-1 in different species, including prokaryotic and eukaryotic sequences. Sequences exhibiting high level of homology in the proximity of the catalytic site were highly considered since it is well appreciated that residues encompassed within catalytic sites are highly conserved among different species. Thus, a multiple sequence alignment was performed, using clustalW software

(available at http://www.ch.embnet.org/software/ClustalW.html), so as to obtain an initial sequence alignment.

Prediction of the secondary structure: Taking into consideration that structures are more conserved than sequences, the initial sequence alignment was refined by prediction algorithms that are based on secondary structures, so as to overcome the non-homology problem. Such a methodology provided for improved quality of the alignment, including regions with low homology. The structure of the reference protein, 1 ALN (ECCDA), contained sequences of β-pleated sheets and α- helix. It was assumed that if the same sequences would be predicted for Apobec-1, the different segments of the secondary structure could be aligned. Hence, it was assumed that if the same sequences would be predicted for Apobec-1, the different segments of the secondary structure could be aligned. Hence, different methods, which provide high probability indices for every amino acids, were used [DSC (Comput Appl Biosci, 1997 Aug;13(4):473-4) and MODELER (Insight II, Accelrys software)]. The secondary structures which were obtained by all of these methods were used for alignment with ECCDA. The results demonstrated a good quality prediction, which validated the method used. The final sequence alignment between Apobec-1 and ECCDA is presented in Figure 1.

It should be noted here that the structural elements (helix and pleated β-sheet) of ECCDA are not found in Apobec-1. However, these elements do not alter the architecture of the catalytic site and conserved residues necessary for the catalytic activity of the enzyme are present (i.e., the global three-dimensional structure of the catalytic site is conserved as well as the key residues implicated in its activity). Construction of a three-dimensional (3D) model: Once the sequence alignment of Apobec-1 to a known 3D structure protein was obtained (Figure 1) the three-dimensional model of the protein was constructed using the MODELER program (Accelrys Insightll 2000, San Diego CA; Sali et al, J. Mol. Biol, 212, 403- 428, 1990), which allows to construct models by homology by extracting spatial constraints from the structural support used, such that the quality of the models depends directly from the quality of the alignment. The MODELER program permits to optimize the position of the amino acids via a simulation recruitment process. A function of « scoring », determined for the assembly of the model as well as for each residue, allows predicting the area of alignment to be adjusted.

A crystal structure, which was deposit in a protein data bank (PDB protein data bank, Accession No. 1ALN, Xiang et al., Biochemistry, 35, 1335, 1996) and in which ECCDA was crystallized in the presence of the inhibitor 3-deazacytidine (DAC), served as a reference for the 3D model. Such a selection of the reference model provides for obtaining a 3D model conformation that would allow virtual screening of Apobec-1 inhibitors.

Since the active form of the deaminase enzyme is a homodimer, the 3D model of Aρobec-1 was constructed under a homodimeric form. In the optimization process for the inhibitor 3-deazacytidine, spatial constraints for 3-deazacytidine, the zinc and the catalytic water molecule within the active site were allowed. The obtained 3D model of the desired Apobec-1 confirmation (in an inhibited form) is presented in Figure 2.

Hypothetic Construction of Pharmacophores - general procedure:

The 3D structure of potential Apobec-1 inhibitors (pharmacophores) was composed by the following Structure Based Focusing (SBF) procedure (general introduction to SBF is available at http://www.sinica.edu.tw/~scimath/msi/ cerius45/sbf/02_theory.html) :

As a first step, characterization of the enzymatic catalytic site was performed by constructing a LUDI interaction carte (Bohm et al., J. Comp. Aided Molec. Design, 6, 69 and 293-606, 1992). The LUDI carte provides determination of the spherical zone of choice, the atoms of the protein which are donors of hydrogen bonds, the atoms of the protein which are acceptors of hydrogen bonds or those belonging to a hydrophobic residue (lipophilic-aliphatic and lipophilic-aromatic residues which are suitable sites for lipophilic interactions). Each of the donor or acceptor hydrogen bonds is represented by two pharmacophoric points, so as to allow taking in consideration the direction of these interactions. The hydrophobic function is represented by a single point. These points represent the spheres which are centered around the pharmacophoric points, such that the radius of these spheres contains a tolerance volume for these atoms.

As a second step, the functions obtained in the LUDI carte were combined one with another so as to create pharmacophoric interactions. These pharmacophoric interactions enable to exclude spheres which represent forbidden zones, namely, zones in which ligands with superior volume or ligands with incompatible form within the active site cannot be bound.

Once the pharmacophoric interactions were defined, they were used for screening commercialized molecules or derivatives and analogs thereof in a variety of databases. Construction of a LUDI interaction Carte: Since the active form of the enzyme is a homodimeric form, which contains two identical active sites, one of the active sites was randomly selected for the LUDI carte.

The interactions described by the LUDI carte are presented in Figure 3. These interactions were carefully examined and thereafter the known inhibitor 3- deazaticitidine was superposed in active site while visualizing the hydrogen bonds between the ligand and the protein.

The superposition showed that most of the potential interactions described by the LUDI carte overlapped the interactions between the 3 -deazaticitidine and the protein. These common interactions were the only interactions used for the hypothetic construction of the pharmacophores and included: one hydrophobic function, three donor functions of hydrogen bonds and two acceptor functions of hydrogen bonds.

Hypotheses of pharmacophores constructions: In order to perform the most selective database screening, six pharmacophoric hypotheses, each including five of the six functions obtained by the LUDI carte, as well as the excluded volumes described above, were constructed, as is presented in Table 6 below. Table 6

Screening Databases: The six hypothetic constructions of the pharmacophores were used in the extensive screening of Maybridge and NCI databases by two methods: CATALYST® and Cerius2 (Accelrys softwares); Other databases have been screened for homology as follows: Maybridge (53,404 molecules), NCI (123,216 molecules), InterBioScreen (318,000 molecules), Florida Center of Heterocyclic Compounds (25,000 molecules) and ChemDiv (288,000 molecules), and ASDI Biosciences (194,000 molecules).

The compounds selected by the screening, which represent potential Apobec-1 inhibitors, are presented in Figures 4-9 and were used to obtain the general structure of an Apobec-1 inhibitor described herein.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

Claims

WHAT IS CLAIMED IS:

1. A method of modulating fat metabolism in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having a general Formulae I, II, III, IN or N:

Formula I Formula II

Formula III

Formula IN

R¹⁴-M-R¹⁵-L-R¹⁶-Mi-R¹⁸-L R¹⁹

Formula N

or a pharmaceutically acceptable salt thereof, wherein,

A and B are each independently Ν or CRa;

W is -CR²⁰R²¹-CR²²R²³-, -CR²⁴=CR²⁵-, -R²⁶R²⁷C-ΝR²⁸-, -R²⁹N-CR³⁰R³¹-, R³²C=N-, -N=CR³³-, -N=N-, -NR³⁴-NR³⁵-, R³⁶N-CR³⁷= or =R³⁸C-NR³⁹, or absent; Q -CR⁴⁰R⁴¹-, -NR⁴²-, -CR⁴³R⁴⁴-CR⁴⁵R⁴⁶-, -CR⁴⁷=CR⁴⁸-, R⁴⁹R⁵⁰C-NR⁵¹-, -

NR⁶², or absent;

_CR67_R68.

V is O, S, Pd, -NR⁶⁹, -CR⁷⁰R⁷¹-, -R⁷²R⁷³C-CR⁷⁴R⁷⁵-, -R⁷⁶R⁷⁷C-CR⁷⁸R⁷⁹-

CR⁸⁰R⁸¹-, -R⁸²R^S3C-CR^S4R⁸⁵-CR⁸⁶R⁸⁷-CR⁸⁸R⁸⁹-, -R⁹⁰C=CR⁹¹-, -R⁹²R⁹³C-NR⁹⁴-

CR ⁵R⁹⁶-, -R⁹⁷R⁹⁸C-NR⁹⁹R¹⁰⁰, -R¹⁰¹R¹⁰²C-NR¹⁰³R¹⁰⁴-CR¹⁰⁵R¹⁰⁶-NR¹⁰⁷R¹⁰⁸- or -O-

G, I and J are each independently -CR¹³⁴R¹³⁵-, -NR¹³⁶-, -CR¹³⁷R¹³⁸-CR¹³⁹R¹⁴⁰- , -CR¹⁴¹=CR¹⁴²-, -R¹⁴³R¹⁴⁴C-NR¹⁴⁵-, -R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-, -R¹⁴⁹C=N-, -N=CR¹⁵⁰-, - N=N-, -NR¹⁵¹-NR¹⁵²-, R¹⁵³N-CR¹⁵⁴- or =R¹⁵⁵C-NR¹⁵⁶, or absent;

Li and L₂ are each independently C, CRc or N;

T is -CR¹⁵⁷R¹⁵⁸R¹⁵⁹, -CR¹⁶⁰R¹⁶¹-CR¹⁶²R¹⁶³R¹⁶⁴ or -R¹⁶⁵;

M is C=O, S=O, P=O, OS, C=N-R¹⁶⁶, S=N-R¹⁶⁷, N=N-R¹⁶⁸ or C=C-R¹⁶⁹;

Mi, L and Li are each independently C=O, S=O, P=O, C=S, C=N-R¹⁷⁰, S=N- R¹⁷¹, N=N-R¹⁷² or C=C-R¹⁷³ or absent; and

Each of Ra, Rb, Re and R^R¹⁷³ is independently is independently selected from the group consisting of hydrogen, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, trihalomethanesulfonamido, guanyl, guanidino, carbohydrate, and amino, or, alternatively, at least two of R², R³ and R²⁰-R⁶² form at least one four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula I, at least two of R⁶³-R¹¹⁰ form at least one three-, four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula II, at least two of R^πl-R form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring and/or at least two of R¹³⁴-R¹⁵⁶ form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula III, and at least two of R³-R¹³ and/or of R¹⁵⁷-R¹⁶⁴ form a three-, four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula IN.

2. The method of claim 1, wherein said compound has a general Formula

3. The method of claim 2, wherein: A and B are each CRa; W is -Ν=CR³³-; and

Q is -CR⁴⁷=CR⁴⁸-.

4. The method of claim 2, wherein: A is N;

B is CRa;

W is -N=CR³³-; and Q is -CR⁴⁷=CR⁴⁸-.

5. The method of claim 2, wherein: A is CRa;

B is N;

W is -R³²C=N-; and

Q is -R⁵⁵C=N.

6. The method of claim 2, wherein: A and B are each CRa; W is -R³²C=N-; and Q is -R ⁹R⁵⁰C-NR⁵¹-.

7. The method of claim 2, wherein:

A and B are each CRa; W is -R²⁶R²⁷C-NR²⁸-; and Q is -R⁴⁹R⁵⁰C-NR⁵¹-.

8. The method of claim 2, wherein: A and B are each CRa;

W is -CR²⁴=CR²⁵; and Q is -CR⁴⁷=CR⁴⁸.

9. The method of claim 2, wherein: A and B are each CRa;

W is =N=CR³³-; and Q is NR⁴².

10. The method of claim 2, wherein: A and B are each CRa;

W is -R³²C=N-; and Q is NR⁴².

11. The method of claim 2, wherein: A and B are each CRa;

W is -R²⁶R²⁷C-NR²⁸-; and Q is NR⁴².

12. The method of claim 2, wherein: A is N;

B is CRa;

W is -CR²⁰R²¹-CR²²R²³-; and

Q is NR⁴².

13. The method of claim 2, wherein: A and B are each N; W is -CR²⁰R²¹-CR²²R²³-; and

QisNR⁴².

14. The method of claim 2, wherein: AisN;

B is CRa;

WisR²⁹N-CR³⁰R³¹;and

Qis-CR⁴⁰R⁴¹.

15. The method of claim 2, wherein: A and B are each N; Wis-R²⁹N-CR³⁰R³¹;and Qis-CR⁴⁰R⁴¹.

16. The method of claim 2, wherein: A and B are each CRa;

W is -R²⁶R²⁷C-NR²⁸-; and Qis-CR⁴⁰R⁴¹.

17. , The method of claim 2, wherein: AisN;

B is CRa;

W is -CR²⁰R²¹-CR²²R²³-; and

Qis-CR⁴⁰R⁴¹.

18. The method of claim 2, wherein: A and B are each N;

Wis -R²⁹N-CR³⁰R³¹; and Qis-CR⁴³R⁴⁴-CR⁴⁵R⁴⁶.

19. The method of claim 1, wherein said compound has the general Formula II.

20. The method of claim 19, wherein:

N is -R⁷²R⁷³C-CR⁷⁴R⁷⁵-; and U is absent.

21. The method of claim 20, wherein: X and Z are each -CR⁶³R⁶⁴-; and Y is O.

22. The method of claim 21, wherein each of R⁶³, R⁶⁴, R⁷², R⁷³, R⁷⁴ and R⁷⁵ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

23. The method of claim 20, wherein: X and Z are each oxygen; and

Y is -CR⁶³R⁶⁴-.

24. The method of claim 23, wherein each of R⁶³, R⁶⁴, R⁷², R⁷³, R⁷⁴ and R⁷⁵ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

25. The method of claim 19, wherein:

N is -R⁸²R⁸³C-CR⁸⁴R⁸⁵-CR⁸⁶R⁸⁷-CR⁸⁸R^8'9-; and U is absent.

26. The method of claim 25, wherein: X and Z are each -CR⁶³R⁶⁴-; and Y is O.

27. The method of claim 26, wherein each of R⁶³, R⁶⁴, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸ and R⁸⁹ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

28. The method of claim 25, wherein: X and Z are each oxygen; and

Y is -CR⁶³R⁶⁴-.

29. The method of claim 28, wherein each of R⁶³, R⁶⁴, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸ and R⁸⁹ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

30. The method of claim 1, wherein said compound has the general Formula III.

31. The method of claim 30, wherein: Li and L₂ are each C;

D is N;

E is -CR^mR¹¹²-;

F is -NR¹¹³-;

J and G are each -N=CR¹⁵⁰-; and

I is absent.

32. The method of claim 30, wherein:

Li and L are each C;

D is -N=CR¹²⁷-;

E is absent;

F is -NR¹¹³-;

J and G are each -N=CR¹⁵⁰-; and

I is absent.

33. The method of claim 30, wherein:

Li and L₂ are each C;

D is -NR¹¹³-;

E is absent;

F is -R¹²⁶C=N-;

J and G are each -N=CR¹⁵⁰-; and

I is absent.

34. The method of claim 30, wherein:

D is-NR¹¹³-;

E is absent;

Fis-CR¹¹⁸=CR¹¹⁹;

J and G are each -N=CR¹⁵⁰-; and

I is absent.

35. The method of claim 30, wherein:

Dis-CR¹¹⁸-CR¹¹⁹;

E is absent;

Fis-NR¹¹³-;

J and G are each -N=CR¹⁵⁰-; and

I is absent.

36. The method of claim 30, wherein:

Li and I_α are each C;

D is -N=CR¹²⁷-;

E is absent;

Fis-NR¹¹³-;

Jis-N=CR¹⁵⁰-;

G is-NR¹³⁶-; and

Iis-CR¹³⁴R¹³⁵.

37. The method of claim 30, wherein:

Lt and are each C;

D is-NR¹¹³-;

E is absent;

F is R¹²⁶C=N-;

Jis-N=CR¹⁵⁰-;

G is-NR¹³⁶-; and

Iis-CR¹³⁴R¹³⁵.

38. The method of claim 30, wherein: Li and L₂ are each C;

Dis-CR¹¹⁸=CR¹¹⁹;

E is absent;

Fis-NR¹¹³-;

Jis-N=CR¹⁵⁰-;

G is-NR¹³⁶-; and

Iis-CR¹³⁴R¹³⁵.

39. The method of claim 30, wherein: Li and L are each C;

D is-NR¹¹³-; E is absent; Fis-CR¹¹⁸=CR¹¹⁹; Jis-N=CR¹⁵⁰-; G is-NR¹³⁶-; and Iis-CR¹³⁴R¹³⁵.

40. The method of claim 30, wherein: Li and L₂ are each C;

D is-NR¹¹³-;

E is absent;

Fis-CR¹²⁶=N-;

Jis-CR¹³⁴R¹³⁵-;

Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-;and

I is-NR¹³⁶.

41. The method of claim 30, wherein: Lt and L₂ are each C;

D is -N=CR¹²⁷-;

E is absent;

Fis-NR¹¹³-;

Jis-CR¹³⁴R¹³⁵-;

Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-;and I is-NR 136

42. The method of claim 30, wherein: Li and L₂ are each C; Dis-CR^mCR¹¹²-;

E is absent; F is -CR¹²⁶=N-; Jis-CR¹³⁴R¹³⁵-; Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-;and I is-NR¹³⁶.

43. The method of claim 30, wherein: Li and _∑ are each C;

D is -R¹²⁶C=N -;

E is absent;

Fis-CR^mCR¹¹²-;

Jis-CR¹³⁴R¹³⁵-;

Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-;and

I is -NR¹³⁶.

44. The method of claim 30, wherein: Li and L₂ are each C;

D is-NR¹¹³-;

E is absent;

F is -CR¹²⁶=N-;

J and G are each CR¹¹⁸=CR¹¹⁹-; and

I is absent.

45. The method of claim 30, wherein: Li and L₂ are each C; Dis-N=CR¹²⁷-;

E is absent; Fis-NR¹¹³-; J and G are each CR¹¹⁸-CR¹¹⁹-; and

I is absent.

46. The method of claim 30, wherein: Li and L₂ are each C; D is -CR^mCR¹¹²-;

E is absent;

F is -CR¹²⁶=N-;

J and G are each CR¹¹⁸=CR¹¹⁹-; and

I is absent.

47. The method of claim 30, wherein: Li and L₂ are each C; D is -R¹²⁶C=N -;

E is absent;

F is -CR^mCR¹¹²-;

J and G are each CR¹¹⁸-CR¹¹⁹-; and

I is absent.

48. The method of claim 1, wherein said compound has the general Formula IN.

49. The method of claim 49, wherein:

Each of R³-R¹³ and of R¹⁵⁷-R¹⁶⁴ is independently selected from the group consisting of hydrogen, alkyl, hydrxyalkyl, carboxy, hydroxy, alkoxy, aryloxy, amido, thiohydroxy, thioalkoxy and carbohydrate.

50. The method of claim 1, wherein said compound has the general Formula N.

51. The method of claim 50, wherein: Mi, , R¹⁸ and R¹⁹ are absent.

52. The method of claim 51 , wherein:

M and L are each C=O.

53. The method of claim 1, wherein said compound is any of the compounds listed in Tables 1-5.

54. The method of claim 1, wherein said modulating of said fat metabolism is effected by inhibiting Apobec-1 activity.

55. The method of claim 1, wherein said modulating of said fat metabolism is by inhibiting apoB48 formation and/or secretion.

56. The method of claim 1, wherein said modulating of said fat metabolism is for a treatment of a condition or disorder selected from the group consisting of overweight, obesity, type II diabetes, hypercholesterolemia, atherosclerosis, hypertension, pancreatitis, hypertriglyceridaema and hyperlipidemia.

57. A method of modulating fat metabolism in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of any of the compounds listed in Tables 1-5.

58. A method of modulating fat metabolism in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound capable of inhibiting Apobec-1 activity.

59. The method of claim 58, wherein said modulating of said fat metabolism is for a treatment of a condition or disorder selected from the group consisting of overweight, obesity, type II diabetes, hypercholesterolemia, atherosclerosis, hypertension, pancreatitis, hypertriglyceridaema and hyperlipidemia.

60. The method of claim 58, wherein said compound has a general Formula I, II, III, IN or N:

Formula I Formula II

Formula UI

Formula IN

R¹⁴-M-R¹⁵-L-R¹⁶-Mι-R¹⁸-Lι-R¹⁹

Formula N

or a pharmaceutically acceptable salt thereof, wherein,

A and B are each independently Ν or CRa;

W is -CR²⁰R²¹-CR²²R²³-, -CR²⁴=CR²⁵-, -R²⁶R²⁷C-ΝR²⁸-, -R²⁹N-CR³⁰R³¹-, - R³²C=N-, -N=CR³³-, -N=N-, -NR³⁴-NR³⁵-, R³⁶N-CR³⁷= or =R³⁸C-NR³⁹, or absent;

V is O, S, Pd, -NR⁶⁹, -CR⁷⁰R⁷¹-, -R⁷²R⁷³C-CR⁷⁴R⁷⁵-, -R⁷⁶R⁷⁷C-CR⁷⁸R⁷⁹- CR⁸⁰R⁸¹-, -R⁸²R⁸³C-CR⁸⁴R⁸⁵-CR⁸⁶R⁸⁷-CR⁸⁸R⁸⁹-, -R⁹⁰C=CR⁹¹-, -R⁹²R⁹³C-NR⁹⁴- CR⁹⁵R⁹⁶-, -R⁹⁷R⁹⁸C-NR⁹⁹R¹⁰⁰, -R¹⁰¹R¹⁰²C-NR¹⁰³R¹⁰⁴-CR¹⁰⁵R¹⁰⁶-NR¹⁰⁷R¹⁰⁸- or -O- _CRIO9_RΠQ.

D, E and F are each independently -CR^mR¹¹²-, -NR¹¹³-, O, S, -CR¹¹⁴R¹¹⁵- CR¹¹⁶R¹¹⁷-, -CR¹¹⁸=CR¹¹⁹-, R¹²⁰R¹²¹C-NR¹²²-, -R¹²³N-CR¹²⁴R¹²⁵-, -R¹²⁶C=N-, - N= R¹²⁷-, -N=N-, -NR¹²⁸-NR¹²⁹-, R¹³⁰N-CR¹³¹= or =R¹³²C-NR¹³³, or absent;

G, I and J are each independently -CR¹³⁴R¹³⁵-, -NR¹³⁶-, -CR¹³⁷R¹³⁸-CR¹³⁹R¹⁴⁰- , -CR¹⁴¹=CR¹⁴²-, -R¹⁴³R¹⁴⁴C-NR¹⁴⁵-, -R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-, -R¹⁴⁹C=N-, -N=CR¹⁵⁰-, - N=N-, -NR¹⁵¹-NR¹⁵²-, R¹⁵³N-CR¹⁵⁴= or =R¹⁵⁵C-NR¹⁵⁶, or absent;

Li and L₂ are each independently C, CRc or N;

M is C=O, S=O, P=O, C=S, C=N-R¹⁶⁶, S=N-R¹⁶⁷, N=N-R¹⁶⁸ or C-C-R¹⁶⁹;

Each of Ra, Rb, Re and R^R¹⁷³ is independently selected from the group consisting of hydrogen, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, trihalomethanesulfonamido, guanyl, guanidino, carbohydrate, and amino, or, alternatively, at least two of R², R³ and R²⁰- R⁶² form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula I, at least two of R⁶³-R¹¹⁰ form at least one three-, four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula II, at least two of R^m-R¹³³ form at least one four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring and/or at least two of R¹³⁴-R¹⁵⁶ form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula III, and at least two of R³- R¹³ and/or of R¹⁵⁷-R¹⁶⁴ form a three-, four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula IN.

61. The method of claim 60, wherein said compound has a general Formula I.

62. The method of claim 61 , wherein: A and B are each CRa; Wis-Ν=CR³³-;and

Q is -CR⁴⁷=CR⁴⁸-.

63. The method of claim 61 , wherein: AisN;

B is CRa;

Wis-N=CR³³-;and Q is -CR⁴⁷=CR⁴⁸-.

64. The method of claim 61 , wherein: A is CRa;

BisN;

Wis-R³C=N-;and

Qis-R⁵⁵C=N.

65. The method of claim 61 , wherein: A and B are each CRa; Wis-R³²C=N-;and Qis-R⁴⁹R⁵⁰C-NR⁵¹-.

66. The method of claim 61 , wherein: A and B are each CRa; Wis-R²⁶R²⁷C-NR²⁸-;and Qis-R⁴⁹R⁵⁰C-NR⁵¹-.

67. The method of claim 61 , wherein:

A and B are each CRa; Wis-CR²⁴=CR²⁵;and Qis-CR⁴⁷=CR⁴⁸.

68. The method of claim 61 , wherein: A and B are each CRa;

W is =N=CR³³-; and Q is NR⁴².

69. The method of claim 61 , wherein: A and B are each CRa; Wis-R³²C=N-;and

QisNR⁴².

70. The method of claim 61 , wherein: A and B are each CRa;

W is -R²⁶R²⁷C-NR²⁸-; and Q is NR⁴².

71. The method of claim 61 , wherein: AisN;

B is CRa;

W is -CR²⁰R²¹-CR²²R²³-; and

Q is NR⁴².

72. The method of claim 61 , wherein: A and B are each N;

W is -CR²⁰R²¹-CR²²R²³-; and QisNR⁴².

73. The method of claim 61 , wherein:

AisN; B is CRa;

WisR²⁹N-CR³⁰R³¹;and

Qis-CR⁰R⁴¹.

74. The method of claim 61 , wherein: A and B are each N;

W is -R²⁹N-CR³⁰R³¹; and Qis-CR⁴⁰R⁴¹.

75. The method of claim 61 , wherein: A and B are each CRa; Wis-R²⁶R²⁷C-NR²⁸-;and Qis-CR⁴⁰R⁴¹.

76. The method of claim 61 , wherein: AisN;

B is CRa;

W is -CR²⁰R²¹-CR²²R²³-; and

Qis-CR⁴⁰R⁴¹.

77. The method of claim 61 , wherein: A and B are each N;

W is -R²⁹N-CR³⁰R³¹; and Qis-CR⁴³R⁴⁴-CR⁴⁵R⁴⁶.

78. The method of claim 60, wherein said compound has the general Formula II.

79. The method of claim 78, wherein: V is -R⁷²R⁷³C-CR⁷⁴R⁷⁵-; and

U is absent.

80. The method of claim 79, wherein: X and Z are each -CR⁶³R⁶⁴- and

Y is O.

81. The method of claim 80, wherein each of R⁶³, R , R⁷², R⁷³, R⁷⁴ and R⁷⁵ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

82. The method of claim 79, wherein: X and Z are each oxygen; and

Y is -CR⁶³R⁶⁴-.

83. The method of claim 82, wherein each of R⁶³, R⁶⁴, R⁷², R⁷³, R⁷⁴ and R⁷⁵ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

84. The method of claim 78, wherein:

N is -R⁸²R⁸³C-CR⁸⁴R⁸⁵-CR⁸⁶R⁸⁷-CR⁸⁸R⁸⁹-; and U is absent.

85. The method of claim 84, wherein: X and Z are each -CR⁶³R⁶⁴-; and Y is O.

86. The method of claim 85, wherein each of R⁶³, R⁶⁴, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸ and R⁸⁹ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

87. The method of claim 84, wherein: X and Z are each oxygen; and

Y is -CR⁶ R⁶⁴-.

88. The method of claim 87, wherein each of R⁶³, R⁶⁴, R⁸², R⁸³, R⁸⁴, R⁸⁵,

R⁸⁶, R⁸⁷, R⁸⁸ and R⁸⁹ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

89. The method of claim 60, wherein said compound has the general Formula III.

90. The method of claim 89, wherein: Li and L₂ are each C;

D is N;

E is -CR^mR¹¹²-;

F is -NR¹¹³-;

J and G are each -N=CR¹⁵⁰-; and

I is absent.

91. The metho of claim 89, wherein: Li and L₂ are each C;

D is -N=CR¹²⁷-;

E is absent;

F is-NR¹¹³-;

J and G are each~N=CR¹⁵⁰-; and

I is absent.

92. The method of claim 89, wherein:

D is -NR¹¹³-;

E is absent;

F is -R¹²⁶C=N-;

J and G are each -N=CR¹⁵⁰-; and

I is absent.

93. The method of claim 89, wherein: D is -NR¹¹³-; E is absent;

Fis-CR¹¹⁸=CR¹¹⁹;

J and G are each -N=CR¹⁵⁰-; and

I is absent.

94. The method of claim 89, wherein: Dis-CR¹¹⁸=CR¹¹⁹;

E is absent;

Fis-NR¹¹³-;

J and G are each -N=CR¹⁵⁰-; and

I is absent.

95. The method of claim 89, wherein: Li and L₂ are each C;

D is -N=CR¹²⁷-; E is absent; Fis-NR¹¹³-; Jis-N=CR¹⁵⁰-; G is-NR¹³⁶-; and Iis-CR¹³⁴R¹³⁵.

96. The method of claim 89, wherein: Li and L₂ are each C;

D is-NR¹¹³-; E is absent; F is R¹²⁶C=N-; J is -N=CR¹⁵⁰-; G is-NR¹³⁶-; and Iis-CR¹³⁴R^13S.

97. The method of claim 89, wherein: Li and are each C; Dis-CR¹¹⁸=CR¹¹⁹; E is absent; Fis-NR¹¹³-; Jis-N=CR¹⁵⁰-; G is -NR¹³⁶-; and Iis-CR¹³⁴R¹³⁵.

98. The method of claim 89, wherein: Li and L₂ are each C;

D is-NR¹¹³-; E is absent; Fis-CR¹¹⁸=CR¹¹⁹; J is -N-CR¹⁵⁰-; G is -NR¹³⁶-; and Iis-CR¹³⁴R¹³⁵.

99. The method of claim 89, wherein: Li and L₂ are each C;

D is-NR¹¹³-;

E is absent;

F is -CR¹²⁶=N-;

Jis-CR¹³⁴R¹³⁵-;

Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-;and

I is-NR¹³⁶.

100. The method of claim 89, wherein:

D is -N=CR¹²⁷-;

E is absent;

Fis-NR¹¹³-;

Jis-CR¹³⁴R¹³⁵-;

Gis-R¹⁴⁶N-CR¹⁷R¹⁴⁸-;and

I is-NR¹³⁶.

101. The method of claim 89, wherein:

Li and L₂ are each C;

Dis-CR^mCR¹¹²-;

E is absent;

F is -CR¹²⁶=N-; is-CR¹³⁴R¹³⁵-;

Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-;and

I is -NR¹³⁶.

102. The method of claim 89, wherein: Li and L₂ are each C; Dis-R¹²⁶C=N-;

E is absent; Fis-CR^mCR¹¹²-; Jis-CR¹³⁴R¹³⁵-; Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-;and I is -NR¹³⁶.

103. The method of claim 89, wherein: Li and L₂ are each C;

D is-NR¹¹³-;

E is absent;

F is -CR¹²⁶=N-;

J and G are each CR¹¹⁸=CR¹¹⁹-; and

I is absent.

104. The method of claim 89, wherein: Li and L₂ are each C;

D is -N=CR¹²⁷-;

E is absent;

Fis-NR¹¹³-;

J and G are each CR¹¹⁸=CR¹¹⁹-; and

I is absent.

105. The method of claim 89, wherein:

D is -CR^mCR¹¹²-;

E is absent;

F is -CR¹²⁶=N-;

J and G are each CR¹¹⁸=CR¹¹⁹-; and

I is absent.

106. The method of claim 89, wherein: Li and L₂ are each C; D is -R¹²⁶C=N -;

E is absent;

F is -CR^mCR¹¹²-;

J and G are each CR¹¹⁸=CR¹¹⁹-; and

I is absent.

107. The method of claim 60, wherein said compound has the general Formula IN.

108. The method of claim 108, wherein:

109. The method of claim 60, wherein said compound has the general Formula N.

110. The method of claim 109, wherein: Mi, Li, R¹⁸ and R¹⁹ are absent.

111. The method of claim 110, wherein: M and L are each C=O.

112. The method of claim 60, wherein said compound is any of the compounds listed in Tables 1-5.

113. A method of inhibiting Apobec-1 activity, the method comprising exposing an Apobec-1 to an inhibitory amount of a compound having a general Formulae I, II, III, IN or N:

Formula I Formula II

Formula III

Formula IN

R¹⁴-M-R¹⁵-L-R¹⁶-Mι-R¹⁸-Lι-R¹⁹

Formula N

or a pharmaceutically acceptable salt thereof, wherein,

A and B are each independently Ν or CRa;

W is -CR²⁰R²¹-CR²²R²³-, -CR²⁴=CR²⁵-, -R²⁶R²⁷C-ΝR²⁸-, -R²⁹N-CR³⁰R³¹- R³²C=N-, -N=CR³³-, -N=N-, -NR³⁴-NR³⁵-, R³⁶N-CR³⁷= or =R³⁸C-NR³⁹, or absent; Q -CR⁴⁰R⁴¹-, -NR⁴²-, -CR⁴³R⁴⁴-CR⁴⁵R⁴⁶-, -CR⁴⁷=CR⁴⁸-, R⁴⁹R⁵⁰C-NR⁵¹-, -

NR⁶², or absent;

_CR109_R110.

Li and L₂ are each independently C, CRc or N;

M is C=O, S=O, P=O, C=S, C=N-R¹⁶⁶, S=N-R¹⁶⁷, N=N-R¹⁶⁸ or C=C-R¹⁶⁹;

Each of Ra, Rb, Re and R^R¹⁷³ is independently is independently selected from the group consisting of hydrogen, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, trihalomethanesulfonamido, guanyl, guanidino, carbohydrate, and amino, or, alternatively, at least two of R², R³ and R²⁰-R⁶² form at least one four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula I, at least two of R⁶³-R¹¹⁰ form at least one three-, four-, five- or six-membered aromatic,

1 1 1 i ii heteroaromatic, alicyclic or heteroalicyclic ring in Formula II, at least two of R -R form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring and/or at least two of R¹³⁴-R¹⁵⁶ form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula III, and at least two of R³-R¹³ and/or of R¹⁵⁷-R¹⁶⁴ form a three-, four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula IN.

114. The method of claim 113, wherein said compound has a general Formula I.

115. The method of claim 114, wherein: A and B are each CRa; W is -Ν=CR³³-; and

Q is -CR⁴⁷=CR⁴⁸-.

116. The method of claim 114, wherein: A is N;

B is CRa;

W is -N=CR³³-; and

Q is -CR⁴⁷=CR⁴⁸-.

117. The method of claim 114, wherein: A is CRa;

B is N;

W is -R³²C=N-; and

Q is -R⁵⁵C=N.

118. The method of claim 114, wherein: A and B are each CRa; W is -R³²C=N-; and

Q is -R⁴⁹R⁵⁰C-NR^S1-.

119. The method of claim 114, wherein:

120. The method of claim 114, wherein: A and B are each CRa; W is -CR²⁴=CR²⁵; and Q is -CR⁴⁷=CR⁴⁸.

121. The method of claim 114, wherein: A and B are each CRa;

W is =N=CR³³-; and Q is NR⁴².

122. The method of claim 114, wherein: A and B are each CRa;

W is -R³²0=N-; and Q is NR⁴².

123. The method of claim 114, wherein: A and B are each CRa; W is -R²⁶R²⁷C-NR²⁸-; and

Q is NR⁴².

124. The method of claim 114, wherein: A is N;

B is CRa;

W is -CR²⁰R²¹-CR²²R²³-; and

Q is NR⁴².

125. The method of claim 114, wherein: A and B are each N; W is -CR²⁰R²¹-CR²²R²³-; and

QisNR 42

126. The method of claim 114, wherein: AisN;

B is CRa;

WisR²⁹N-CR³⁰R³¹;and

Qis-CR⁴⁰R⁴¹.

127. The method of claim 114, wherein: A and B are each N; Wis-R²⁹N-CR³⁰R³¹;and Qis-CR⁴⁰R⁴¹.

128. The method of claim 114, wherein: A and B are each CRa;

W is -R²⁶R²⁷C-NR²⁸-; and Qis-CR⁴⁰R⁴¹.

129. The method of claim 114, wherein: AisN;

B is CRa;

W is -CR²⁰R²¹-CR²²R²³-; and

Qis-CR⁴⁰R⁴¹.

130. The method of claim 114, wherein: A and B are each N;

W is -R²⁹N-CR³⁰R³¹; and Qis-CR⁴³R⁴⁴-CR⁴⁵R⁴⁶.

131. The method of claim 113, wherein said compound has the general Formula II.

132. The method of claim 131, wherein:

N is -R⁷²R⁷³C-CR⁷⁴R⁷⁵-; and U is absent.

133. The method of claim 132, wherein: X and Z are each -CR⁶³R⁶⁴-; and Y is O.

134. The method of claim 133, wherein each of R⁶³, R⁶⁴, R⁷², R⁷³, R⁷⁴ and R⁷⁵ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

135. The method of claim 132, wherein: X and Z are each oxygen; and Y is -CR⁶³R⁶⁴-.

136. The method of claim 135, wherein each of R⁶³, R⁶⁴, R⁷², R⁷³, R⁷⁴ and R⁷⁵ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

137. The method of claim 131, wherein:

V is -R⁸²R⁸³C-CR⁸⁴R⁸⁵-CR⁸⁶R⁸⁷-CR⁸⁸R⁸⁹-; and U is absent.

138. The method of claim 137, wherein: X and Z are each -CR⁶³R⁶⁴-; and Y is O.

139. The method of claim 138, wherein each of R⁶³, R⁶⁴, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸ and R⁸⁹ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

140. The method of claim 137, wherein: X and Z are each oxygen; and

Y is -CR⁶³R⁶⁴-.

141. The method of claim 140, wherein each of R⁶³, R⁶⁴, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸ and R⁸⁹ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

142. The method of claim 113, wherein said compound has the general Formula III.

143. The method of claim 142, wherein: Li and L₂ are each C;

D is N;

E is -CR^1UR¹¹²-;

F is -NR 113

J and G are eac -NOR , 1¹50 -; and I is absent.

144. The method of claim 142, wherein: Li and L^ are each C;

D is -N=CR¹²⁷-;

E is absent;

F is -NR¹¹³-;

J and G are each -N=CR¹⁵⁰-; and

I is absent.

145. The method of claim 142, wherein: Li and L2 are each C;

D is -NR¹¹³-;

E is absent;

F is -R¹²⁶C=N-;

J and G are each -N=CR¹⁵⁰-; and

I is absent.

146. The method of claim 142, wherein:

D is-NR¹¹³-;

E is absent;

Fis-CR¹¹⁸=CR¹¹⁹;

J and G are each -N=CR¹⁵⁰-; and

I is absent.

147. The method of claim 142, wherein: Dis-CR¹¹⁸=CR¹¹⁹;

E is absent;

Fis-NR¹¹³-;

J and G are each -N=CR¹⁵⁰-; and

I is absent.

148. The method of claim 142, wherein:

D is -N=CR¹²⁷-; E is absent; Fis-NR¹¹³-; Jis-N=CR¹⁵⁰-; G is -NR¹³⁶-; and Iis-CR¹³⁴R¹³⁵.

149. The method of claim 142, wherein: Li and L^ are each C;

D is-NR¹¹³-; E is absent; F is R¹²⁶C=N-; Jis-N=CR¹⁵⁰-; G is -NR¹³⁶-; and Iis-CR¹³⁴R¹³⁵.

150. The method of claim 142, wherein: Li and L₂ are each C;

Dis-CR¹¹⁸=CR¹¹⁹;

E is absent;

Fis-NR¹¹³-;

Jis-N=CR¹⁵⁰-;

G is-NR¹³⁶-; and

Iis-CR¹³⁴R¹³⁵.

151. The method of claim 142, wherein: Li and L₂ are each C;

D is-NR¹¹³-; E is absent; Fis-CR¹¹⁸=CR¹¹⁹; J is -N=CR¹⁵⁰-; G is -NR¹³⁶-; and Iis-CR¹³⁴R¹³⁵.

152. The method of claim 142, wherein: Li and L₂ are each C;

D is-NR¹¹³-;

E is absent;

Fis-CR¹²⁶=N-;

Jis-CR¹³⁴R¹³⁵-;

Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-;and

I is-NR¹³⁶.

153. The method of claim 142, wherein:

D is -N=CR¹²⁷-;

E is absent;

Fis-NR¹¹³-;

Jis-CR¹³⁴R¹³⁵-;

Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-;and I is-NR 136

154. The method of claim 142, wherein:

Dis-CR^mCR¹¹²-;

155. The method of claim 142, wherein: Li and L₂ are each C; Dis-R¹²⁶C=N-;

E is absent; Fis-CR^mCR¹¹²-; J is -CR¹³R¹³⁵-; Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-;and I is-NR¹³⁶.

156. The method of claim 142, wherein:

Li and L₂ are each C;

D is-NR¹¹³-;

E is absent;

Fis-CR¹²⁶=N-;

J and G are each CR¹¹⁸=CR¹¹⁹-; and

I is absent.

157. The method of claim 142, wherein:

Li and L are each C;

Dis-N=CR¹²⁷-;

E is absent;

Fis-NR¹¹³-; J and G are each CR¹¹⁸=CR¹¹⁹-; and

I is absent.

158. The method of claim 142, wherein:

D is -CR^mCR¹¹²-;

E is absent;

F is -CR¹²⁶=N-;

J and G are each CR¹¹⁸=CR¹¹⁹-; and

I is absent.

159. The method of claim 142, wherein: Li and L₂ are each C; D is -R¹²⁶C=N -;

E is absent;

F is -CR CR¹¹²-;

J and G are each CR¹¹⁸=CR¹¹⁹-; and

I is absent.

160. The method of claim 113, wherein said compound has the general Formula IN.

161. The method of claim 161, wherein:

162. The method of claim 113, wherein said compound has the general Formula V.

163. The method of claim 162, wherein: Mi, Li, R¹⁸ and R¹⁹ are absent.

164. The method of claim 163 , wherein:

M and L are each C=O.

165. The method of claim 113, wherein said compound is any of the compounds listed in Tables 1-5.

166. A method of inhibiting Apobec-1 activity, the method comprising exposing an Apobec-1 to an inhibitory amount of any of the compounds listed in Tales 1-5.

167. A pharmaceutical composition for the treatment or prevention of a condition or disorder in which modulating fat metabolism is beneficial, comprising, as an active ingredient, a compound capable of inhibiting an Apobec-1 activity, and a pharmaceutically acceptable carrier.

168. The pharmaceutical composition of claim 167, wherein said condition or disorder is selected from the group consisting of overweight, obesity, type II diabetes, hypercholesterolemia, atherosclerosis, hypertension, pancreatitis, hypertriglyceridaema and hyperlipidemia.

169. The pharmaceutical composition of claim 167, wherein said compound has a general Formulae I, II, III, IN or N:

Formula I Formula II

Formula III

Formula IN

R¹⁴-M-R¹⁵-L-R¹⁶-Mι-R^ω-Lι-R¹⁹

Formula N

or a pharmaceutically acceptable salt thereof, wherein,

A and B are each independently Ν or CRa;

Q -CR⁴⁰R⁴¹-, -NR⁴²-, -CR⁴³R⁴⁴-CR ⁵R⁴⁶-, -CR⁴⁷=CR⁴⁸-, R⁴⁹R⁵⁰C-NR⁵¹-, - R⁵²N-CR⁵³R⁵⁴, -R⁵⁵C=N-, -N=CR⁵⁶-, -N=N-, -NR⁵⁷-NR⁵⁸-, R⁵⁹N-CR⁶⁰= or =R⁶¹C- NR⁶², or absent;

V is O, S, Pd, -NR⁶⁹, -CR⁷⁰R⁷¹-, -R⁷²R⁷³C-CR⁷⁴R⁷⁵-, -R⁷⁶R⁷⁷C-CR⁷⁸R⁷⁹- CR⁸⁰R⁸¹-, -R⁸²R⁸³C-CR⁸⁴R⁸⁵-CR⁸⁶R⁸⁷-CR⁸⁸R⁸⁹-, -R⁹⁰C=CR⁹¹-, -R⁹²R⁹³C-NR⁹⁴- CR⁹⁵R⁹⁶-, -R⁹⁷R⁹⁸C-NR"R¹⁰⁰, -R¹⁰¹R¹⁰²C-NR¹⁰³R¹⁰⁴-CR¹⁰⁵R¹⁰⁶-NR¹⁰⁷R¹⁰⁸- or -O-

_CR109_R110.

CR¹¹⁶R¹¹⁷-, -CR¹¹⁸=CR¹¹⁹-, R¹²⁰R¹²¹C-NR¹²²-, -R¹²³N-CR¹²⁴R¹²⁵-, -R¹²⁶C=N-, -

N=CR¹²⁷-, -N=N-, -NR¹²⁸-NR¹²⁹-, R¹³⁰N-CR¹³¹= or =R¹³²C-NR¹³³, or absent;

G, I and J are each independently -CR¹³⁴R¹³⁵-, -NR¹³⁶-, -CR¹³⁷R¹³⁸-CR¹³⁹R¹⁴⁰-

, -CR¹⁴¹=CR¹⁴²-, -R¹⁴³R¹⁴⁴C-NR¹⁴⁵-, -R¹⁴⁶N-CR^{1 7}R¹⁴⁸-, -R¹⁴⁹C=N-, -N=CR¹⁵⁰-, -

N=N-, -NR¹⁵¹-NR¹⁵²-, R¹⁵³N-CR¹⁵⁴= or =R¹⁵⁵C-NR¹⁵⁶, or absent;

Li and L₂ are each independently C, CRc or N;

T is -CR¹⁵⁷R¹⁵⁸R¹⁵⁹, -CR¹⁶⁰R¹⁶¹-CR¹⁶²R¹⁶³R^16'

M is C=O, S=O, P=O, C=S, C=N-R¹⁶⁶, S=N-R^lo/, N=N-R^10δ or C=C-R^X

Mi, L and Li are each independently C=O, SO, P=O, C=S, C=N-R 170^υ, S=N- R¹⁷¹, N=N-R¹⁷² or C=C-R¹⁷³ or absent; and

Each of Ra, Rb, Re and R^R¹⁷³ is independently is independently selected from the group consisting of hydrogen, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, trihalomethanesulfonamido, guanyl, guanidino, carbohydrate, and amino, or, alternatively, at least two of R , R and R -R form at least one four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula I, at least two of R -R form at least one three-, four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula II, at least two of R^ul-R¹³³ form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring and/or at least two of R¹³⁴-R¹⁵⁶ form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula III, and at least two of R³-R¹³ and/or of R¹⁵⁷-R¹⁶⁴ form a three-, four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula IN.

170. The pharmaceutical composition of claim 169, wherein said compound has a general Formula I.

171. The pharmaceutical composition of claim 170, wherein:

A and B are each CRa; W is -N=CR³³-; and Q is -CR⁴⁷OR⁴⁸-.

172. The pharmaceutical composition of claim 170, wherein: AisN;

B is CRa;

W is -NOR³³-; and

Q is -CR⁴⁷OR⁴⁸-.

173. The pharmaceutical composition of claim 170, wherein: A is CRa;

BisN;

W is -R³²C=N-; and

Qis-R⁵⁵C=N.

174. The pharmaceutical composition of claim 170, wherein: A and B are each CRa;

Wis-R³²C=N-;and Qis-R⁴⁹R⁵⁰C-NR⁵¹-.

175. The pharmaceutical composition of claim 170, wherein: A and B are each CRa;

W is -R²⁶R²⁷C-NR²⁸-; and Qis-R⁴⁹R⁵⁰C-NR⁵¹-.

176. The pharmaceutical composition of claim 170, wherein: A and B are each CRa;

Wis-CR²⁴OR²⁵;and Q is -CR⁴⁷OR⁴⁸.

177. The pharmaceutical composition of claim 170, wherein: A and B are each CRa;

Wis=NOR³³-;and

Q is NR⁴².

178. The pharmaceutical composition of claim 170, wherein: A and B are each CRa;

W is -R³²C=N-; and Q is NR⁴².

179. The pharmaceutical composition of claim 170, wherein: A and B are each CRa;

Wis-R²⁶R²⁷C-NR²⁸-;and Q is NR⁴².

180. The pharmaceutical composition of claim 170, wherein: AisN;

B is CRa;

W is -CR²⁰R²¹-CR²²R²³-; and

Q is NR⁴².

181. The pharmaceutical composition of claim 170, wherein: A and B are each N;

W is -CR²⁰R²¹-CR²²R²³-; and Q is NR⁴².

182. The pharmaceutical composition of claim 170, wherein: AisN;

B is CRa;

WisR²⁹N-CR³⁰R³¹;and

Qis-CR⁴⁰R⁴¹.

183. The pharmaceutical composition of claim 170, wherein: A and B are each N; Wis-R )2^z9^yN_T-C-.P-DΛ30TJ3^J1¹;.and Qis-CR⁴⁰R⁴¹.

184. The pharmaceutical composition of claim 170, wherein: A and B are each CRa;

Wis-R²⁶R²⁷C-NR²⁸-;and Qis-CR⁴⁰R⁴¹.

185. The pharmaceutical composition of claim 170, wherein: AisN;

B is CRa;

W is -CR²⁰R²¹-CR²²R²³-; and

Qis-CR⁴⁰R⁴¹.

186. The pharmaceutical composition of claim 170, wherein: A and B are each N;

Wis -R²⁹N-CR³⁰R³¹; and Qis-CR⁴³R⁴⁴-CR⁴⁵R⁴⁶.

187. The pharmaceutical composition of claim 169, wherein said compound has the general Formula II.

188. The pharmaceutical composition of claim 187, wherein: V is -R⁷²R⁷³C-CR⁷⁴R⁷⁵-; and

U is absent.

189. The pharmaceutical composition of claim 188, wherein: X and Z are each -CR⁶³R⁶⁴-; and

YisO.

190. The pharmaceutical composition of claim 189, wherein each of R⁶³, R⁶⁴, R⁷², R⁷³, R⁷⁴ and R⁷⁵ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

191. The pharmaceutical composition of claim 188, wherein: X and Z are each oxygen; and

Y is -CR⁶³R⁶⁴-.

192. The pharmaceutical composition of claim 191, wherein each of R , R⁶⁴, R⁷², R⁷³, R⁷⁴ and R⁷⁵ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

193. The pharmaceutical composition of claim 187, wherein: N is -R⁸²R⁸³C-CR⁸⁴R⁸⁵-CR⁸⁶R⁸⁷-CR⁸⁸R⁸⁹-; and

U is absent.

194. The pharmaceutical composition of claim 193, wherein: X and Z are each -CR⁶³R⁶⁴-; and

Y is O.

195. The pharmaceutical composition of claim 194, wherein each of R , R⁶⁴, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸ and R⁸⁹ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

196. The pharmaceutical composition of claim 193 , wherein: X and Z are each oxygen; and

Y is -CR⁶³R⁶⁴-

197. The pharmaceutical composition of claim 196, wherein each of R⁶³, R⁶⁴, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸ and R⁸⁹ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

198. The pharmaceutical composition of claim 169, wherein said compound has the general Formula III.

199. The pharmaceutical composition of claim 198, wherein: Li and L₂ are each C;

DisN;

Eis-CR^mR¹¹²-;

Fis-NR¹¹³-;

J and G are each -NOR¹⁵⁰-; and

I is absent.

200. The pharmaceutical composition of claim 198, wherein: Li and L₂ are each C;

D is -NOR¹²⁷-;

E is absent;

Fis-NR¹¹³-;

J and G are each -NOR¹⁵⁰-; and

I is absent.

201. The pharmaceutical composition of claim 198, wherein: Li and ₂ are each C;

D is-NR¹¹³-;

E is absent;

Fis-R¹²⁶C=N-;

J and G are each -NOR¹⁵⁰-; and

I is absent.

202. The pharmaceutical composition of claim 198, wherein: D is-NR¹¹³-;

E is absent;

Fis-CR¹¹⁸OR¹¹⁹;

J and G are each -NOR¹⁵⁰-; and

I is absent.

203. The pharmaceutical composition of claim 198, wherein: D Diiss-CRR^111188;OR¹¹⁹ E is absent; F is -NR¹¹³-;

J and G are each -NOR¹⁵⁰-; and

I is absent.

204. The pharmaceutical composition of claim 198, wherein: Li and L₂ are each C;

D is -NOR¹²⁷-; E is absent; F is -NR¹¹³-; J is -NOR¹⁵⁰-; G is -NR¹³⁶-; and I is -CR¹³⁴R¹³⁵.

205. The pharmaceutical composition of claim 198, wherein: Li and L₂ are each C;

D is -NR¹¹³-; E is absent; F is R¹²⁶C=N-;

J is -NOR 150 .

G is -NR¹³⁶-; and

I is -CR¹³⁴R¹³⁵.

206. The pharmaceutical composition of claim 198, wherein: Li and L₂ are each C;

D is R¹¹⁸OR¹¹⁹; E is absent; F is -NR¹¹³-; J is -NOR¹⁵⁰-; G is -NR¹³⁶-; and I is -CR¹³⁴R¹³⁵.

207. The pharmaceutical composition of claim 198, wherein: Li and L₂ are each C; D is-NR¹¹³-;

E is absent;

Fis-CR¹¹⁸OR¹¹⁹;

J is -NOR¹⁵⁰-;

G is-NR¹³⁶-; and

Iis-CR¹³⁴R¹³⁵.

208. The pharmaceutical composition of claim 198, wherein: Li and L₂ are each C;

D is-NR¹¹³-;

E is absent;

Fis-CR¹²⁶=N-;

J is -CR¹³⁴R¹³⁵-;

Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-;and

I is-NR¹³⁶.

209. The pharmaceutical composition of claim 198, wherein:

D is -NOR¹²⁷-; E is absent; Fis-NR¹¹³-; Jis-CR¹³⁴R¹³⁵-; Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-;and • I is-NR¹³⁶.

210. The pharmaceutical composition of claim 198, wherein: Li and L₂ are each C;

Dis R^mCR¹¹²-; E is absent;

Fis-CR¹²⁶=N-;

Jis-CR¹³⁴R¹³⁵-;

Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-;and

I is-NR¹³⁶.

211. The pharmaceutical composition of claim 198, wherein:

Li and L₂ are each C;

D is -R¹²⁶C=N -;

E is absent;

Fis-CR^mCR¹¹²-;

Jis-CR¹³⁴R¹³⁵-;

Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-;and

I is-NR¹³⁶.

212. The pharmaceutical composition of claim 198, wherein: Li and L₂ are each C;

D is-NR¹¹³-;

E is absent;

Fis-CR¹²⁶=N-;

J and G are each CR¹¹⁸OR¹¹⁹-; and

I is absent.

213. The pharmaceutical composition of claim 198, wherein: Li and L₂ are each C;

Dis -NOR¹²⁷-;

E is absent;

Fis-NR¹¹³-;

J and G are each CR¹¹⁸OR¹¹⁹-; and

I is absent.

214. The pharmaceutical composition of claim 198, wherein: Li and L₂ are each C;

Dis-CR^mCR¹¹²-;

E is absent;

F is -CR¹²⁶=N-;

J and G are each CR¹¹⁸ R¹¹⁹-; and

I is absent.

215. The pharmaceutical composition of claim 198, wherein:

Li and I-^ are each C;

D is -R¹²⁶C=N -;

E is absent;

F is -CR^mCR¹¹²-;

J and G are each CR¹¹⁸ R¹¹⁹-; and

I is absent.

216. The pharmaceutical composition of claim 169, wherein said compound has the general Formula IN.

217. The pharmaceutical composition of claim 217, wherein:

218. The pharmaceutical composition of claim 169, wherein said compound has the general Formula V.

219. The pharmaceutical composition of claim 218, wherein: Mi, Li, R¹⁸ and R¹⁹ are absent.

220. The pharmaceutical composition of claim 219, wherein: M and L are each CO-.

221. The pharmaceutical composition of claim 169, wherein said compound is any of the compounds listed in Tables 1-5.

222. A pharmaceutical composition for the treatment or prevention of a condition or disorder in which modulating fat metabolism is beneficial, comprising, as an active ingredient, any of the compound listed in Tabled 1-5, and a pharmaceutically acceptable carrier.

223. A pharmaceutical composition for the treatment or prevention of a condition or disorder in which modulating fat metabolism is beneficial, comprising, a pharmaceutically acceptable carrier, and, as an active ingredient, a compound having a general Formulae I, II, III, IN or N:

Formula I Formula II

Formula III

Formula IN

R^-M-R^-L-R^-Mi-R^-L R¹⁹

Formula N

or a pharmaceutically acceptable salt thereof, wherein,

A and B are each independently Ν or CRa;

W is -CR²⁰R²¹-CR²²R²³-, -CR²⁴OR²⁵-, -R²⁶R²⁷C-ΝR²⁸-, -R²⁹N-CR³⁰R³

R ,3^J2^Z

or absent; Q -CR⁴⁰R⁴¹-, -NR⁴²-, -CR⁴ R⁴⁴-CR⁴⁵R⁴⁶-, -CR⁴⁷ R⁴⁸-, R⁴⁹R⁵⁰C-NR⁵¹-,

-R , 5³5³,C- =N-,

-N=N-, -NR 5^D7'-NR , 5^D8⁸-,

or =R ,6°1'C, -

NR •.62 , or absent; X, Y and Z are each independently O, NRb, S, -CR⁶³R⁶⁴- or -R⁶⁵R⁶⁶C-

CR⁶⁷R⁶⁸;

CR⁸⁰R⁸¹-, -R⁸²R⁸³C-CR⁸⁴R⁸⁵-CR⁸⁶R⁸⁷-CR⁸⁸R⁸⁹-, -R⁹⁰C R⁹¹-, -R⁹²R⁹³C-NR⁹⁴-

_CR109_R110.

D, E and F are each independently -CR^1UR¹¹²-, -NR¹¹³-, O, S, -CR¹¹⁴R¹¹⁵- CR¹¹⁶R¹¹⁷-, -CR¹¹⁸OR¹¹⁹-, R¹²⁰R¹²¹C-NR¹²²-, -R¹²³N-CR¹²⁴R¹²⁵-, -R¹²⁶C=N-, - NOR¹²⁷-, -N=N-, -NR¹²⁸-NR¹²⁹-, R¹³⁰N-CR¹³¹= or =R¹³²C-NR¹³³, or absent;

G, I and J are each independently -CR¹³⁴R¹³⁵-, -NR¹³⁶-, -CR¹³⁷R¹³⁸-CR¹³⁹R¹⁴⁰- , -CR¹⁴¹OR¹⁴²-, -R¹⁴³R¹⁴⁴C-NR¹⁴⁵-, -R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-, -R¹⁴⁹C=N-, -NOR¹⁵⁰-, - N=N-, -NR¹⁵¹-NR¹⁵²-, R¹⁵³N-CR¹⁵⁴= or =R¹⁵⁵C-NR¹⁵⁶, or absent;

Li and La are each independently C, CRc or N;

T is R¹⁵⁷R¹⁵⁸R¹⁵⁹, R¹⁶⁰R¹⁶¹-CR¹⁶²R¹⁶³R¹⁶⁴or-R¹⁶⁵;

M is OO, SO-, PO, C=S, C=N-R¹⁶⁶, S=N-R¹⁶⁷, N=N-R¹⁶⁸ or C -R¹⁶⁹;

Mi, L and ave each independently CO-, SO-, P=0, C=S, C=N-R¹⁷⁰, S=N- R¹⁷¹, N=N-R¹⁷² or CO-R¹⁷³ or absent; and

Each of Ra, Rb, Re and R^!-R¹⁷³ is independently is independently selected from the group consisting of hydrogen, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, trihalomethanesulfonamido, guanyl, guanidino, carbohydrate, and amino, or, alternatively, at least two of R², R³ and R²⁰-R⁶² form at least one four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula I, at least two of R⁶³-R¹¹⁰ form at least one three-, four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula II, at least two of R -R form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring and/or at least two of R¹³⁴-R¹⁵⁶ form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula III, and at least two of R³-R¹³ and/or of R¹⁵⁷-R¹⁶⁴ foπn a three-, four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Foπnula IN.

224. The pharmaceutical composition of claim 223, wherein said compound has a general Formula I.

225. The pharmaceutical composition of claim 224, wherein: A and B are each CRa;

W is -NOR³³-; and Q is -CR⁴⁷OR⁴⁸-.

226. The pharmaceutical composition of claim 224, wherein: A is N;

B is CRa;

W is -NOR³³-; and

Q is -CR⁴⁷OR⁴⁸-.

227. The pharmaceutical composition of claim 224, wherein: A is CRa;

B is N;

W is -R³²C=N-; and Q is -R⁵⁵C=N.

228. The pharmaceutical composition of claim 224, wherein: A and B are each CRa;

W is -R³²C=N-; and Q is -R⁴⁹R⁵⁰C-NR⁵¹-.

229. The pharmaceutical composition of claim 224, wherein: A and B are each CRa; W is -R²⁶R²⁷C-NR²⁸-; and Qis-R⁴⁹R⁵⁰C-NR⁵¹-.

230. The pharmaceutical composition of claim 224, wherein: A and B are each CRa;

Wis-CR²⁴OR²⁵;and Qis-CR⁴⁷OR⁴⁸.

231. The pharmaceutical composition of claim 224, wherein: A and B are each CRa;

W is =NOR³³-; and QisNR⁴².

232. The pharmaceutical composition of claim 224, wherein: A and B are each CRa;

Wis-R³²C=N-;and Q is NR⁴².

233. The pharmaceutical composition of claim 224, wherein: A and B are each CRa;

W is -R²⁶R²⁷C-NR²⁸-; and QisNR⁴².

234. The pharmaceutical composition of claim 224, wherein: AisN;

B is CRa;

W is -CR⁰R²¹-CR²²R²³-; and

QisNR⁴².

235. The pharmaceutical composition of claim 224, wherein: A and B are each N;

W is -CR²⁰R²¹-CR²²R²³-; and QisNR⁴².

236. The pharmaceutical composition of claim 224, wherein:

AisN;

B is CRa;

WisR²⁹N-CR³⁰R³¹;and

Qis-CR⁴⁰R⁴¹.

237. The pharmaceutical composition of claim 224, wherein:

A and B are each N;

Wis-R²⁹N-CR³⁰R³¹;and

Qis-CR⁴⁰R⁴¹.

238. The pharmaceutical composition of claim 224, wherein:

A and B are each CRa;

Wis-R²⁶R²⁷C-NR²⁸-;and

Qis-CR⁴⁰R⁴¹.

239. The pharmaceutical composition of claim 224, wherein: AisN;

B is CRa;

W is -CR²⁰R²¹-CR²²R²³-; and

Qis-CR⁴⁰R⁴¹.

240. The pharmaceutical composition of claim 224, wherein: A and B are each N;

W is -R²⁹N-CR³⁰R³¹; and Qis-CR⁴³R⁴⁴-CR⁴⁵R⁴⁶.

241. The pharmaceutical composition of claim 223, wherein said compound has the general Formula II.

242. The pharmaceutical composition of claim 241 , wherein: V is -R⁷²R⁷³C-CR⁷⁴R⁷⁵-; and

U is absent.

243. The pharmaceutical composition of claim 242, wherein:

X and Z are each -CR⁶³R⁶⁴-; and

Y is O.

244.. The pharmaceutical composition of claim 243, wherein each of R , R⁶⁴, R⁷², R⁷³, R⁷⁴ and R⁷⁵ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

245. The pharmaceutical composition of claim 242, wherein: X and Z are each oxygen; and

Y is -CR⁶³R⁶⁴-.

246. The pharmaceutical composition of claim 245, wherein each of R , R⁶⁴, R⁷², R⁷³, R⁷⁴ and R⁷⁵ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

247. The pharmaceutical composition of claim 241 , wherein: N is -R⁸²R⁸³C-CR⁸⁴R⁸⁵-CR⁸⁶R⁸⁷-CR⁸⁸R⁸⁹-; and

U is absent.

248. The pharmaceutical composition of claim 247, wherein: X and Z are each -CR⁶³R⁶⁴-; and

Y is O.

249. The pharmaceutical composition of claim 248, wherein each of R ³, R⁶⁴, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸ and R⁸⁹ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

250. The pharmaceutical composition of claim 247, wherein: X and Z are each oxygen; and

Y is -CR⁶³R⁶⁴-.

251. The pharmaceutical composition of claim 250, wherein each of R ,

R⁶⁴, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸ and R⁸⁹ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

252. The pharmaceutical composition of claim 223, wherein said compound has the general Formula III.

253. The pharmaceutical composition of claim 252, wherein: Li and L₂ are each C;

D is N;

E is -CR^mR¹¹²-;

F is -NR¹¹³-;

J and G are each -NOR¹⁵⁰-; and

I is absent.

254. The pharmaceutical composition of claim 252, wherein: Li and L₂ are each C;

D is -NOR¹²⁷-;

E is absent;

F is -NR¹¹³-;

J and G are each -NOR¹⁵⁰-; and

I is absent.

255. The pharmaceutical composition of claim 252, wherein: Li and L₂ are each C;

D is -NR¹¹³-;

E is absent;

F is -R¹²⁶C=N-;

J and G are each -NOR¹⁵⁰-; and

I is absent.

256. The pharmaceutical composition of claim 252, wherein: D is -NR¹¹³-; E is absent;

Fis-CR¹¹⁸OR¹¹⁹;

J and G are each -NOR¹⁵⁰-; and

I is absent.

257. The pharmaceutical composition of claim 252, wherein: Dis-CR¹¹⁸OR¹¹⁹;

E is absent;

Fis-NR¹¹³-;

J and G are each -NOR¹⁵⁰-; and

I is absent.

258. The pharmaceutical composition of claim 252, wherein: Li and L₂ are each C;

D is -NOR¹²⁷-; E is absent; Fis-NR¹¹³-; J is -NOR¹⁵⁰-; G is-NR¹³⁶-; and Iis-CR¹³⁴R¹³⁵.

259. The pharmaceutical composition of claim 252, wherein: Li and L₂ are each C;

D is-NR¹¹³-; E is absent; F is R¹²⁶C=N-; J is -NOR¹⁵⁰-; G is -NR¹³⁶-; and Iis-CR¹³⁴R¹³⁵.

260. The pharmaceutical composition of claim 252, wherein: Li and L₂ are each C;

Dis-CR¹¹⁸OR¹¹⁹; E is absent;

Fis-NR¹¹³-;

J is -NOR¹⁵⁰-;

G is-NR¹³⁶-; and

Iis-CR¹³⁴R¹³⁵.

261. The pharmaceutical composition of claim 252, wherein: Li and 1^ are each C;

D is -NR¹¹³-; E is absent; Fis-CR¹¹⁸OR¹¹⁹; J is -NOR¹⁵⁰-; G is-NR¹³⁶-; and Iis-CR¹³⁴R¹³⁵.

262. The pharmaceutical composition of claim 252, wherein: Li and L₂ are each C;

D is-NR¹¹³-;

E is absent;

Fis-CR¹²⁶=N-;

Jis-CR¹³⁴R¹³⁵-;

Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-;and

I is-NR¹³⁶.

263. The pharmaceutical composition of claim 252, wherein: Li and 1-₂ are each C;

D is -NOR¹²⁷-; E is absent; F is -NR¹¹³ -;

Jis-CR¹³⁴R¹³⁵-; G G iiss --RR¹¹⁴⁴⁶⁶NN-CR¹⁴⁷R¹⁴⁸~; and I is-NR¹³⁶.

264. The pharmaceutical composition of claim 252, wherein:

Li and L₂ are each C;

Dis R^mCR¹¹²-;

E is absent;

F is -CR¹²⁶=N-;

Jis-CR¹³⁴R¹³⁵-;

Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-;and

I is -NR¹³⁶.

265. The pharmaceutical composition of claim 252, wherein:

D is -R¹²⁶C=N -; - E is absent; Fis-CR^mCR¹¹²-; Jis R¹³⁴R¹³⁵-; Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-;and I is -NR¹³⁶.

266. The pharmaceutical composition of claim 252, wherein: Li and L₂ are each C;

D is-NR¹¹³-;

E is absent;

F is -CR¹²⁶=N-;

J and G are each CR¹¹⁸OR¹¹⁹-; and

I is absent.

267. The pharmaceutical composition of claim 252, wherein:

Dis -NOR¹²⁷-;

E is absent;

Fis-NR¹¹³-;

J and G are each CR¹¹⁸OR¹¹⁹-; and

I is absent.

268. The pharmaceutical composition of claim 252, wherein:

Li and L₂ are each C;

D is -CR^mCR¹¹²-;

E is absent;

F is -CR¹²⁶=N-;

J and G are each CR¹¹⁸OR¹¹⁹-; and

I is absent.

269. The pharmaceutical composition of claim 252, wherein: Li and L₂ are each C;

D is -R¹²⁶C=N -;

E is absent;

F is -CR CR¹¹²-;

J and G are each CR¹¹⁸ R¹¹⁹-; and

I is absent.

270. The pharmaceutical composition of claim 223, wherein said compound has the general Formula IV.

271. The pharmaceutical composition of claim 271, wherein:

272. The pharmaceutical composition of claim 223, wherein said compound has the general Formula V.

273. The pharmaceutical composition of claim 272, wherein: Mi, Li, R¹⁸ and R¹⁹ are absent.

274. The pharmaceutical composition of claim 273, wherein: M and L are each CO-.

275. The pharmaceutical composition of claim 223, wherein said compound is any of the compounds listed in Tables 1-5.

276. A method of identifying a candidate compound for modulating fat metabolism by inhibiting Apobec-1 activity, the method comprising: obtaining a set of structural coordinates defining the three-dimensional structure of at least the active site cavity of Apobec-1; and computationally identifying a compound which is capable of specifically binding to said three-dimensional structure of said active site cavity, thereby identifying the candidate compound for modulating fat metabolism by inhibiting Apobec-1 activity.

277. The method of claim 276, wherein at least said active site cavity of Apobec-1 is defined by amino acid coordinates 31-116 of Apobec-1.

278. The method of claim 276, wherein at least said active site cavity of Apobec-1 is defined by amino acid coordinates 1-142 of Apobec-1.

279. The method of claim 276, wherein said at least the active site cavity of Apobec-1 is defined by amino acid coordinates 59-98 of Apobec-1.

280. The method of claim 276, wherein said at least the active site cavity of Apobec-1 is defined by at least five amino acid residues present in the sequence defined by amino acid coordinates 59-98 of Apobec-1.

281. The method of claim 280, wherein said at least five amino acid residues are as set forth in histidine 61, cysteine 93, cysteine 96, valine 62 and glutamate 63.

282. The method of claim 276, wherein identifying is effected by: determining a position and orientation of at least one pharmacophore interacting moiety in said active site cavity; and identifying a compound that both spatially and chemically fits to said three- dimensional structure of said active site cavity.

283. The method of claim 282, wherein said at least one pharmacophore interacting moiety comprises a plurality of pharmacophore interacting moieties, whereby said identifying said compound that chemically binds to said three- dimensional structure of said active site cavity is based on at least one of a plurality of combinations of said plurality of pharmacophore interacting moieties.

284. The method of claim 282, wherein said determining a position and orientation of said at least one pharmacophore interacting moiety is by computational means.

285. The method of claim 276, wherein said identifying is by computational means.

286. The method of claim 276, wherein said obtaining said set of structural coordinates is by computational means.

287. A computer readable medium comprising a data storing device storing therein in a retrievable or executable format a computational representation of a set of structural coordinates defining a three-dimensional structure of at least an active site cavity of Apobec-1 and of at least one pharmacophore interacting moiety in said active site cavity of Apobec-1.

288. The computer readable medium of claim 287, wherein at least said active site cavity of Apobec-1 is defined by amino acid coordinates 31-116 of Apobec-1.

289. The computer readable medium of claim 287, wherein at least said active site cavity of Apobec-1 is defined by amino acid coordinates 1-142 of Apobec- 1.

290. The computer readable medium of claim 287, wherein said at least the active site cavity of Apobec-1 is defined by amino acid coordinates 59-98 of Apobec- 1.

291. The computer readable medium of claim 287, wherein said at least the active site cavity of Apobec-1 is defined by at least five amino acid residues present in the sequence defined by amino acid coordinates 59-98 of Apobec-1.

292. The computer readable medium of claim 291, wherein said at least five amino acid residues are as set forth in histidine 61, cysteine 93, cysteine 96, valine 62 and glutamate 63.

293. A computer readable medium comprising a data storing device storing, in a retrievable or executable format, data including a set of structure coordinates defining at least a portion of a three-dimensional structure of Apobec-1.

294. The computer readable medium of claim 293, wherein said three- dimensional structure of Apobec-1, is at least an active site cavity of Apobec-1.

295. The computer readable medium of claim 294, wherein at least said active site cavity of Apobec-1 is defined by amino acid coordinates 31-116 of Apobec-1.

296. The computer readable medium of claim 294, wherein at least said active site cavity of Apobec-1 is defined by amino acid coordinates 1-142 of Apobec- 1.

297. The computer readable medium of claim 294, wherein said at least the active site cavity of Apobec-1 is defined by amino acid coordinates 59-98 of Apobec- 1.

298. The computer readable medium of claim 294, wherein said at least the active site cavity of Apobec-1 is defined by at least five amino acid residues present in the sequence defined by amino acid coordinates 59-98 of Apobec-1.

299. The computer readable medium of claim 298, wherein said at least five amino acid residues are as set forth in histidine 61, cysteine 93, cysteine 96, valine 62 and glutamate 63.

300. A computer readable medium comprising a data storing device storing in a retrievable or executable format, data including a set of structural coordinates defining at least a portion of a three-dimensional structure of Apobec-1 complexed with an Apobec-1 inhibitor.

301. The computer readable medium of claim 300, wherein said three- dimensional structure of Apobec-1, is at least an active site cavity of Apobec-1.

302. The computer readable medium of claim 301, wherein at least said active site cavity of Apobec-1 is defined by amino acid coordinates 31-116 of Aρobec-1.

303. The computer readable medium of claim 301, wherein at least said active site cavity of Apobec-1 is defined by amino acid coordinates 1-142 of Apobec- 1.

304. The computer readable medium of claim 301, wherein said at least the active site cavity of Apobec-1 is defined by amino acid coordinates 59-98 of Apobec- 1.

305. The computer readable medium of claim 301, wherein said at least the active site cavity of Apobec-1 is defined by at least five amino acid residues present in the sequence defined by amino acid coordinates 59-98 of Apobec-1.

306. The computer readable medium of claim 305, wherein said at least five amino acid residues are as set forth in histidine 61, cysteine 93, cysteine 96, valine 62 and glutamate 63.

307. The computer readable medium of claim 300, wherein said data including said set of structural coordinates defining at least said portion of said three- dimensional structure of Apobec-1 is derived from the set of coordinates presented in the Table of Figures 7-132.

308. The computer readable medium of claim 300 or 307, wherein said Apobec-1 inhibitor has a general Formulae I, II, III, IN and N:

Formula I Foπnula II

Formula III

Formula IN

R¹⁴-M-R¹⁵-L-R¹⁶-Mι-R¹⁸-Lι-R¹⁹

Formula N or a pharmaceutically acceptable salt thereof, wherein,

A and B are each independently N or CRa;

W is -CR²⁰R²¹-CR²²R²³-, -CR²⁴OR²⁵-, -R²⁶R²⁷C-NR²⁸-, -R²⁹N-CR³⁰R³¹-, - R³²C=N-, -NOR³³-, -N=N-, -NR³⁴-NR³⁵-, R³⁶N-CR³⁷= or =R³⁸C-NR³⁹, or absent;

Q -CR⁴⁰R⁴¹-, -NR⁴²-, -CR⁴³R⁴ -CR ⁵R⁴⁶-, -CR⁴⁷OR⁴⁸-, R⁴⁹R⁵⁰C-NR⁵¹-, - R⁵²N-CR⁵³R⁵⁴, -R⁵⁵C=N-, -NOR⁵⁶-, -N=N-, -NR⁵⁷-NR⁵⁸-, R⁵⁹N-CR⁶⁰= or =R⁶¹C- NR⁶², or absent;

V is O, S, Pd, -NR⁶⁹, -CR⁷⁰R⁷¹-, -R⁷ R⁷³C-CR⁷⁴R⁷⁵-, -R⁷⁶R⁷⁷C-CR⁷⁸R⁷⁹- CR⁸⁰R⁸¹-, -R⁸²R⁸³C-CR⁸⁴R⁸⁵-CR⁸⁶R⁸⁷-CR⁸⁸R⁸⁹-, -R⁹⁰COR⁹¹-, -R⁹²R⁹³C-NR⁹⁴- CR⁹⁵R⁹⁶-, -R⁹⁷R⁹⁸C-NR⁹⁹R¹⁰⁰, -R¹⁰¹R¹⁰²C-NR¹⁰³R¹⁰⁴-CR¹⁰⁵R¹⁰⁶-NR¹⁰⁷R¹⁰⁸- or -O-

_CR109_R110.

D, E and F are each independently -CR^mR¹¹²-, -NR¹¹³-, O, S, -CR¹¹ R¹¹⁵- CR¹¹⁶R¹¹⁷-, -CR¹¹⁸ R¹¹⁹-, R^{1 0}R^{1 1}C-NR¹²²-, -R¹²³N-CR¹²⁴R¹²⁵-, -R¹²⁶C=N-, - NOR¹²⁷-, -N=N-, -NR¹²⁸-NR¹²⁹-, R¹³⁰N-CR¹³¹= or =R¹³²C-NR¹³³, or absent;

G, I and J are each independently -CR¹³⁴R¹³⁵-, -NR¹³⁶-, -CR¹³⁷R¹³⁸-CR¹³⁹R¹⁴⁰- , -CR¹⁴¹OR¹⁴²-, -R¹⁴³R¹⁴⁴C-NR¹⁴⁵-, -R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-, -R¹⁴⁹0=N-, -NOR¹⁵⁰-, - N=N-, -NR^1S1-NR¹⁵²-, R¹⁵³N-CR¹⁵⁴= or =R¹⁵⁵C-NR¹⁵⁶, or absent;

Li and L₂ are each independently C, CRc or N;

T is OR¹⁵⁷R¹⁵⁸R¹⁵⁹, -CR¹⁶⁰R¹⁶¹-CR¹⁶²R¹⁶³R¹⁶⁴ or -R¹⁶⁵;

M is C=O, SO-, PO, C=S, C=N-R¹⁶⁶, S=N-R¹⁶⁷, N=N-R¹⁶⁸ or CO-R¹⁶⁹;

Mi, L and Li are each independently CO-, SO, PO, C=S, C=N-R¹⁷⁰, S=N- R¹⁷¹, N=N-R¹⁷² or CO-R¹⁷³ or absent; and

Each of Ra, Rb, Re and R^R¹⁷³ is independently is independently selected from the group consisting of hydrogen, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azo, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphonium, ketoester, carbonyl, thiocarbonyl, ester, ether, carboxy, thiocarboxy, thioether, thiocarbamate, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, trihalomethanesulfonamido, guanyl, guanidino, carbohydrate, and amino, or, alternatively, at least two of R², R³ and R²⁰-R⁶² form at least one four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula I, at least two of R⁶³-R¹¹⁰ form at least one three-, four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula II, at least two of R^m-R¹³³ form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring and/or at least two of R¹³⁴-R¹⁵⁶ form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula III, and at least two of R³-R¹³ and/or of R¹⁵⁷-R¹⁶⁴ form a three-, four-, five- or six- membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring in Formula IN.

309. The computer readable medium of claim 308, wherein said compound has a general Formula I.

310. The computer readable medium of claim 309, wherein: A and B are each CRa;

W is -NOR³³-; and Q is -CR⁴⁷OR⁴⁸-.

311. The computer readable medium of claim 309, wherein: A is N;

B is CRa;

W is -NOR³³-; and

Q is -CR⁴⁷OR⁴⁸-.

312. The computer readable medium of claim 309, wherein: A is CRa;

B is ;

W is -R³²C=N-; and Q is -R⁵⁵C=N.

313. The computer readable medium of claim 309, wherein:

A and B are each CRa; W is -R³²C=N-; and Qis-R⁴⁹R⁵⁰C-NR⁵¹-.

314. The computer readable medium of claim 309, wherein: A and B are each CRa;

W is -R²⁶R²⁷C-NR²⁸-; and Qis-R⁴⁹R⁵⁰C-NR⁵¹-.

315. The computer readable medium of claim 309, wherein: A and B are each CRa;

Wis-CR²⁴OR²⁵;and Qis-CR⁴⁷OR⁴⁸.

316. The computer readable medium of claim 309, wherein: A and B are each CRa;

Wis=N R³³-;and QisNR⁴².

317. The computer readable medium of claim 309, wherein: A and B are each CRa;

Wis-R³²C-N-;and QisNR⁴².

318. The computer readable medium of claim 309, wherein: A and B are each CRa;

W is -R²⁶R²⁷C-NR²⁸-; and QisNR⁴².

319. The computer readable medium of claim 309, wherein: AisN;

B is CRa; W is -CR²⁰R²¹-CR²²R²³-; and

QisNR⁴².

320. The computer readable medium of claim 309, wherein: A and B are each N;

W is -CR²⁰R²¹-CR²²R²³-; and Q is NR⁴².

321. The computer readable medium of claim 309, wherein: AisN;

B is CRa;

Wis ²⁹N-CR³⁰R³¹;and

Qis-CR⁰R⁴¹.

322. The computer readable medium of claim 309, wherein: A and B are each N;

W is -R²⁹N-CR³⁰R³¹; and Qis-CR⁴⁰R⁴¹.

323. The computer readable medium of claim 309, wherein: A and B are each CRa;

W is -R²⁶R²⁷C-NR²⁸-; and Qis-CR⁴⁰R⁴¹.

324. The computer readable medium of claim 309, wherein: AisN;

B is CRa;

W is -CR²⁰R²¹-CR²²R²³-; and

Qis-CR⁴⁰R⁴¹.

325. The computer readable medium of claim 309, wherein: A and B are each N;

W is -R²⁹N-CR³⁰R³¹; and Q is -CR⁴³R⁴⁴-CR⁴⁵R⁴⁶.

326. The computer readable medium of claim 308, wherein said compound has the general Formula II.

327. The computer readable medium of claim 326, wherein: N is -R⁷²R⁷³C-CR⁷⁴R⁷⁵-; and

U is absent.

328. The computer readable medium of claim 327, wherein:

X X aanndd Z Z are each -CR⁶³R⁶⁴- and

Y is O.

329. The computer readable medium of claim 328, wherein each of R , R⁶⁴, R⁷², R⁷³, R⁷⁴ and R⁷⁵ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

330. The computer readable medium of claim 327, wherein: X and Z are each oxygen; and

Y is -CR⁶³R⁶⁴-.

331. The computer readable medium of claim 330, wherein each of R , R⁶⁴, R⁷², R⁷³, R⁷⁴ and R⁷⁵ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

332. The computer readable medium of claim 326, wherein: V V iiss --RR⁸⁸²²RR⁸⁸³C-CR⁸⁴R⁸⁵-CR⁸⁶R⁸⁷-CR⁸⁸R⁸⁹-; and U is absent.

333. The computer readable medium of claim 332, wherein:

X and Z are each -CR⁶³R⁶⁴-; and

Y is O.

334. The computer readable medium of claim 333, wherein each of R ,

335. The computer readable medium of claim 332, wherein:

X and Z are each oxygen; and

Y is -CR⁶³R⁶⁴-.

336. The computer readable medium of claim 335, wherein each of R , R⁶⁴, R⁸², R⁸³, R⁸⁴, R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸ and R⁸⁹ is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, hydrogen and hydroxyalkyl.

337. The computer readable medium of claim 308, wherein said compound has the general Formula III.

338. The computer readable medium of claim 337, wherein: Li and L^ are each C;

D is N;

E is -CR^U1R¹¹²-;

F is -NR¹¹³-;

J and G are each -NOR¹⁵⁰-; and

I is absent.

339. The computer readable medium of claim 337, wherein: Li and L₂ are each C;

D is -NOR¹²⁷-;

E is absent;

F is -NR¹¹³-;

J and G are each -NOR¹⁵⁰-; and

I is absent.

340. The computer readable medium of claim 337, wherein: Li and L₂ are each C; D is -NR¹¹³-;

E is absent;

F is -R¹²⁶C=N-;

J and G are each -NOR¹⁵⁰-; and

I is absent.

341. The computer readable medium of claim 337, wherein: D is -NR¹¹³-;

E is absent;

F is -CR¹¹⁸ R¹¹⁹;

J and G are each -NOR¹⁵⁰-; and

I is absent.

342. The computer readable medium of claim 337, wherein: D is -CR¹¹⁸OR¹¹⁹;

E is absent;

F is -NR¹¹³-;

J and G are each -NOR¹⁵⁰-; and

I is absent.

343. The computer readable medium of claim 337, wherein:

344. The computer readable medium of claim 337, wherein:

D is -NR¹¹³-; E is absent;

J is -NOR 150

G is-NR¹³⁶-; and Iis-CR¹³⁴R¹³⁵.

345. The computer readable medium of claim 337, wherein: Li and are each C;

Dis-CR¹¹⁸OR¹¹⁹; E is absent; Fis-NR¹¹³-; J is -NOR¹⁵⁰-; G is-NR¹³⁶-; and Iis-CR¹³⁴R¹³⁵.

346. The computer readable medium of claim 337, wherein: Li and L are each C;

D is-NR¹¹³-; E is absent; Fis-CR¹¹⁸OR¹¹⁹; J is -NOR¹⁵⁰-; G is -NR¹³⁶-; and Iis R¹³⁴R¹³⁵.

347. The computer readable medium of claim 337, wherein: Li and L₂ are each C;

D is-NR¹¹³-;

E is absent; Fis-CR¹²⁶=N-; Jis-CR¹³⁴R¹³⁵-; G G iiss --RR¹¹⁴⁴⁶⁶IN-CR¹⁴⁷R¹⁴⁸-;and I is-NR¹³⁶.

348. The computer readable medium of claim 337, wherein: Li and L₂ are each C; Dis -NOR¹²⁷-; E is absent;

Fis-NR¹¹³-; Jis-CR¹³⁴R¹³⁵-; Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁸-;and I is -NR¹³⁶.

349. The computer readable medium of claim 337, wherein: Li and 1^ are each C; Dis-CR^mCR¹¹²-; E is absent;

Fis-CR¹²⁶=N-;

Jis-CR¹⁴R¹³⁵-; Gis-R¹⁴⁶N-CR¹⁴⁷R¹⁴⁸-;and

I is-NR 136

350. The computer readable medium of claim 337, wherein: Li and L₂ are each C;

Dis-R¹²⁶C=N-;

E is absent;

Fis-CR^mCR¹¹²-;

Jis-CR¹³⁴R¹³⁵-;

Gis-R¹⁶N-CR¹⁴⁷R¹⁸-;and

I is-NR¹³⁶.

351. The computer readable medium of claim 337, wherein: Li and L₂ are each C;

D is-NR¹¹³-;

E is absent;

Fis-CR¹²⁶=N-;

J and G are each CR¹¹⁸OR¹¹⁹-; and

I is absent.

352. The computer readable medium of claim 337, wherein:

Li and 1-^ are each C;

D is -NOR¹²⁷-;

E is absent;

F is -NR¹¹³ -;

J and G are each CR¹¹⁸OR¹¹⁹-; and

I is absent.

353. The computer readable medium of claim 337, wherein: Li and L₂ are each C;

D is -CR^mCR¹¹²-;

E is absent;

F is -CR¹²⁶=N-;

J and G are each CR¹¹⁸OR¹¹⁹-; and

I is absent.

354. The computer readable medium of claim 337, wherein: Li and L₂ are each C;

D is -R¹²⁶C=N -;

E is absent;

F is -CR^mCR¹¹²-;

J and G are each CR¹¹⁸OR^{J 19}-; and

I is absent.

355. The computer readable medium of claim 308, wherein said compound has the general Formula IN.

356. The computer readable medium of claim 356, wherein:

357. The computer readable medium of claim 308, wherein said compound has the general Formula N.

358. The computer readable medium of claim 357, wherein: Mi, Li, R¹⁸ and R¹⁹ are absent.

359. The computer readable medium of claim 358, wherein: M and L are each CO.

360. The computer readable medium of claim 308, wherein said compound is any of the compounds listed in Tables 1-5.

361. A method of identifying a candidate compound for inhibiting Apobec- 1 activity, the method comprising: obtaining a set of structural coordinates defining a three-dimensional atomic structure of at least the active site cavity of Apobec-1; and computationally screening a plurality of compounds for a compound capable of specifically binding said active site cavity, thereby identifying the candidate compound for inhibiting Apobec-1 activity.

362. A computing platform for generating a three-dimensional model of at least the active site cavity of Apobec-1, the computing platform comprising: a data-storage device storing data comprising a set of structural coordinates defining at least said active site cavity of Apobec-1; and a processing unit being for generating the three-dimensional model from said data stored in said data-storage device.

363. A computing platform for generating a three-dimensional model of at least a portion of Apobec-1 complexed with an Apobec-1 inhibitor, the computing platform comprising: a data-storage device storing data comprising a set of structural coordinates defining at least a portion of a three-dimensional structure of at least the active site of Apobec-1 complexed with said Apobec-1 inhibitor; and a processing unit being for generating the three-dimensional model from said data stored in said data-storage device.

364. A method of identifying a candidate compound for modulating fat metabolism by inhibiting Apobec-1 activity, the method comprising: identifying a compound that spatially and chemically binds to a three- dimensional structure of the active site cavity of Apobec-1; and biologically assaying said compound for its activity in inhibiting Apobec-1 and/or in modulating fat metabolism.

365. The method of claim 364, wherein said biologically assaying said compound in effected by an assay selected from the group consisting of: determining fat levels in a biological sample; determining apoB expression; determining apoB secretion; and determining cytidine deaminase activity.