WO2020074403A1 - Molécules modulatrices de l'appétit - Google Patents

Molécules modulatrices de l'appétit Download PDF

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Publication number
WO2020074403A1
WO2020074403A1 PCT/EP2019/076992 EP2019076992W WO2020074403A1 WO 2020074403 A1 WO2020074403 A1 WO 2020074403A1 EP 2019076992 W EP2019076992 W EP 2019076992W WO 2020074403 A1 WO2020074403 A1 WO 2020074403A1
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methyl
alkyl
compound according
item
compound
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PCT/EP2019/076992
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English (en)
Inventor
Florian Engert
Josua JORDI
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Universität Zürich
President And Fellows Of Harvard College
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Publication of WO2020074403A1 publication Critical patent/WO2020074403A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to small molecule compounds capable of modulating appetite in a vertebrate animal, particularly in a mammal.
  • the invention further relates to the use of the compounds of the invention in methods of treatment of eating disorders, and as a food additive for human consumption or animal husbandry.
  • Mainstream drug discovery efforts focus on protein targets using simple in vitro or cellular screens to identify small molecules or biologies as modulators.
  • the quality of the target correlates with success and, consequently, an in-depth molecular characterization underlying a phenotype is a prerequisite.
  • Behaviors such as food intake are not understood at the molecular level, which strongly limits the reductionist approach of target-driven drug discovery.
  • Up to the present target-based approaches are far less successful at identifying first-in-class drugs compared to holistic and unbiased phenotypic strategies, particularly in CNS drug discovery.
  • Furthermore in vivo drug efficacy is a major obstacle, because traditional drug screening methods do not mimic whole organism dynamics e.g. the blood-brain barrier.
  • the objective of the present invention is to provide means and methods to screen for appetite regulators. This objective is attained by the subject-matter of the independent claims of the present specification.
  • the present invention relates to compounds which regulate appetite and their uses.
  • the present invention relates to a compound characterized by a general formula
  • R 4 is an unsubstituted or methyl-substituted 5- or 6-membered aryl or heteroaryl
  • R 5 is an unsubstituted or substituted aryl with the substituent being F, Cl, C1-C3 alkyl, C1-C3 alkyl ether, vinyl or allyl ether;
  • R 6 is COR c or CONHR c with R c being an unsubstituted or C1-C3 alkyl substituted heteroaryl.
  • R 4 is selected from
  • R 5 is selected from
  • the compound is characterized by a formula (201 )
  • the present invention relates to a compound characterized by a general formula (100)
  • R 1 is selected from unsubstituted C1-C4 alkyl or amino-/hydroxy- and/or fluoro-substituted C1-C4 alkyl, unsubstituted phenyl or phenyl substituted by C 1 -C 3 unsubstituted alkyl, NR n 2 , wherein each R N independently from the other is H or C 1 -C 3 unsubstituted alkyl;
  • R 21 , R 22 , R 23 , R 22‘ , and R 21 are independently selected from H, halogen, unsubstituted C 1 -C 3 alkyl or O-alkyl, fluoro-substituted C 1 -C 3 alkyl or O-alkyl, particularly R 21 , R 22 , R 23 , R 22‘ , and R 21 are independently selected from H, F, Cl, methyl, CF 3 , ethyl, O-methyl, and O-CF 3 ; more particularly R 21 and R 22 ’ are independently selected from halogen, unsubstituted C 1 -C 3 alkyl or O-alkyl, fluoro-substituted C 1 -C 3 alkyl or O-alkyl and the other ones are H, or R 23 is selected from halogen, unsubstituted C 1 -C 3 alkyl or
  • R 31 , R 32 , R 33 , R 32 ‘, and R 31 ’ are independently selected from H, F, Cl, CF 3 , methyl, ethyl, O-methyl, and O-CF 3 ;
  • D is NH, N-methyl or O
  • R 3 is NHR D orOR D , wherein R D is a 5- or 6-membered unsubstituted or amino-/hydroxy- or F-substituted cyclic alkyl.
  • R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4- methylphenyl, and N-dimethyl; and/or
  • R 2 is selected from
  • R 3 is selected from
  • the compound is characterized by a formula (101 )
  • the present invention relates to a compound as diclosed above in the first or second aspect for use for the treatment of an eating disorder, cachexia or anorexia, particularly anorexia nervosa, bulimia, cachexia associated with tumour disease, viral or bacterial infection; cachexia associated with a psychological disorder, particularly cachexia associated with stress, depression, or anxiety; cachexia associated with, particularly a gastrointestinal disorder selected from peptic ulcer, GERD, and ulcerative colitis; medication-induced anorexia associated with chemotherapy, administration of a laxative or amphetamine drug.
  • the present invention relates to a foodstuff or food additive comprising a compound as diclosed above in the first or second aspect, particularly for use in animal farming.
  • the present invention relates to a compound characterized by a general formula (300)
  • X is S, O or N-methyl
  • R 7 is H, F, Cl or C 1 -C 3 alkyl
  • R 8 is H, F, Cl or C 1 -C 3 alkyl
  • R 9 is NH 2 , NH-methyl, OH or methyl;
  • R 10 is
  • R 101 , R 102 , R 103 , R 102 ‘, and R 101 ’ are independently selected from H, F, Cl, CF 3 , methyl, and NO2.
  • X is selected from S, O, and N-methyl
  • R 7 is selected from H and methyl; and/or R 8 is selected from H, Cl, and methyl; and/or R 9 is selected from NH 2 ; NH-methyl, OH, methyl; and/or R 10 is selected from
  • X is S; R7 is methyl; R8 is methyl; R9 is NH2; and R10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4-fluorophenyl, and 3- nitrophenyl, preferably 4-nitrophenyl.
  • the compound is characterized by a formula (302)
  • the present invention relates to a compound as disclosed in the third aspect for use for the treatment of a disease selected from obesity, binge eating disorder, metabolic syndrome, prediabetes, type 2 diabetes, dyslipidaemia, hypertension, cardiovascular disease, non alcoholic fatty liver disease, polycystic ovary syndrome, female infertility, male hypogonadism, obstructive sleep apnoea, asthma/reactive airway disease, osteoarthritis, urinary stress incontinence, gastroesophageal reflux disease, and depression.
  • a disease selected from obesity, binge eating disorder, metabolic syndrome, prediabetes, type 2 diabetes, dyslipidaemia, hypertension, cardiovascular disease, non alcoholic fatty liver disease, polycystic ovary syndrome, female infertility, male hypogonadism, obstructive sleep apnoea, asthma/reactive airway disease, osteoarthritis, urinary stress incontinence, gastroesophageal reflux disease, and depression.
  • the present invention also relates to a pharmaceutical composition comprising any compound as disclosed herein and to their use as a drug.
  • the present invention further relates to a non-therapeutic method for modulating the appetite in a subject comprising administering a compound as disclosed herein.
  • the appetite can be increased and the compound is a compound according to the first or second aspect.
  • the appetite can be decreased and the compound is a compound according to the third aspect.
  • dpf is an abbreviation for days-post-fertilization.
  • the zebrafish eggs are fertilized and the growing zebrafish larvae are analysed at certain time period after their fertilization measured in dpf.
  • ANOVA is an abbreviation for analysis of variance. ANOVA comprises certain statistical methods used to analyse the difference of group means in a sample for statistical significance.
  • C 1 -C 4 alkyl in the context of the present specification signifies a saturated linear or branched hydrocarbon having 1 , 2, 3 or 4 carbon atoms, wherein in certain embodiments one carbon-carbon bond may be unsaturated and one CH2 moiety may be exchanged for oxygen (ether bridge) or nitrogen (NH, or NR with R being methyl, ethyl, or propyl; amino bridge).
  • Non- limiting examples for a C 1 -C 4 alkyl are methyl, ethyl, propyl, prop-2-enyl, n-butyl, 2-methylpropyl, tert- butyl, but-3-enyl, prop-2-inyl and but-3-inyl.
  • a C 1 -C 4 alkyl is a methyl, ethyl, propyl or butyl moiety.
  • a C1-C6 alkyl in the context of the present specification signifies a saturated linear or branched hydrocarbon having 1 , 2, 3, 4, 5 or 6 carbon atoms, wherein one carbon-carbon bond may be unsaturated and one CH2 moiety may be exchanged for oxygen (ether bridge) or nitrogen (NH, or NR with R being methyl, ethyl, or propyl; amino bridge).
  • Non-limiting examples for a C1-C6 alkyl include the examples given for C 1 -C 4 alkyl above, and additionally 3-methylbut-2-enyl, 2- methylbut-3-enyl, 3-methylbut-3-enyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 1 ,1-dimethylpropyl, 1 ,2-dimethylpropyl, 1 ,2-dimethylpropyl, pent-4-inyl, 3-methyl-2-pentyl, and 4-methyl-2-pentyl.
  • a C5 alkyl is a pentyl or cyclopentyl moiety and a O Q alkyl is a hexyl or cyclohexyl moiety.
  • unsubstituted C n alkyl when used herein in the narrowest sense relates to the moiety - C n H2 n - if used as a bridge between moieties of the molecule, or -C n H2 n+i if used in the context of a terminal moiety. It may still contain fewer H atoms if a cyclical structure or one or more (non- aromatic) double bonds are present.
  • unsubstituted C n alkyl and substituted C n alkyl include a linear alkyl comprising or being linked to a cyclical structure, for example a cyclopropane, cyclobutane, cyclopentane or cyclohexane moiety, unsubstituted or substituted depending on the annotation or the context of mention, having linear alkyl substitutions.
  • N, O or other hetero atom in the linear chain or cyclical structure adds up to n.
  • Me is methyl CH3
  • Et is ethyl -CH2CH3
  • Prop is propyl -(Chh ⁇ CHs (n-propyl, n-pr) or -CH(CH3)2 (iso- propyl, i-pr), but is butyl -C 4 H 9 , -(CH 2 ) 3 CH3, -CHCH3CH2CH3, -CH 2 CH(CH 3 ) 2 or -C(CH 3 ) 3 .
  • substituted alkyl in its broadest sense refers to an alkyl as defined above in the broadest sense that is covalently linked to an atom that is not carbon or hydrogen, particularly to an atom selected from N, O, F, B, Si, P, S, Cl, Br and I, which itself may be -if applicable- linked to one or several other atoms of this group, or to hydrogen, or to an unsaturated or saturated hydrocarbon (alkyl or aryl in their broadest sense).
  • substituted alkyl refers to an alkyl as defined above in the broadest sense that is substituted in one or several carbon atoms by groups selected from amine NH 2 , alkylamine NHR, imide NH, alkylimide NR, amino(carboxyalkyl) NHCOR or NRCOR, hydroxyl OH, oxyalkyl OR, oxy(carboxyalkyl) OCOR, carbonyl O and its ketal or acetal (OR) 2 , nitril CN, isonitril NC, cyanate CNO, isocyanate NCO, thiocyanate CNS, isothiocyanate NCS, fluoride F, choride Cl, bromide Br, iodide I, phosphonate PO3H2, PO3R2, phosphate OPO3H2 and OPO3R2, sulfhydryl SH, suflalkyl SR, sulfoxide SOR, sulf
  • amino substituted alkyl or hydroxyl substituted alkyl refers to an alkyl according to the above definition that is modified by one or several amine or hydroxyl groups NH 2 , NHR, NR 2 or OH, wherein the R substituent as used in the current paragraph, different from other uses assigned to R in the body of the specification, is itself an unsubstituted or substituted C 1 to C 12 alkyl in its broadest sense, and in a narrower sense, R is methyl, ethyl or propyl unless otherwise specified.
  • An alkyl having more than one carbon may comprise more than one amine or hydroxyl.
  • the term“substituted alkyl” refers to alkyl in which each C is only substituted by at most one amine or hydroxyl group, in addition to bonds to the alkyl chain, terminal methyl, or hydrogen.
  • carboxyl substituted alkyl refers to an alkyl according to the above definition that is modified by one or several carboxyl groups COOH, or derivatives thereof, particularly carboxylamides CONH 2 , CONHR and CONR 2 , or carboxylic esters COOR, with R having the meaning as laid out in the preceding paragraph and different from other meanings assigned to R in the body of this specification.
  • Non-limiting examples of amino-substituted alkyl include -CH 2 NH 2 , -CH 2 NHMe, -CH 2 NHEt, -CH 2 CH 2 NH 2 , -CH 2 CH 2 NHMe, -CH 2 CH 2 NHEt, -(CH 2 ) 3 NH 2 , -(CH 2 ) 3 NHMe, -(CH 2 ) 3 NHEt, -CH 2 CH(NH 2 )CH 3 , -CH 2 CH(NHMe)CH 3 , -CH 2 CH(NHEt)CH 3 , -(CH 2 )3CH 2 NH 2 ,
  • -CH 2 CH(CH 2 NHEt) 2 for terminal moieties and -CH 2 CHNH 2 -, -CH 2 CHNHMe-, -CH 2 CHNHEt- for an amino substituted alkyl moiety bridging two other moieties.
  • Non-limiting examples of hydroxy-substituted alkyl include -CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 ) 3 OH, -CH 2 CH(OH)CH 3 , -(CH 2 ) 4 OH, -CH(CH 2 OH)CH 2 CH 3 , -CH 2 CH(CH 2 OH)CH 3 ,
  • halogen-substituted alkyl refers to an alkyl according to the above definition that is modified by one or several halogen atoms selected (independently) from F, Cl, Br, I.
  • fluoro substituted alkyl refers to an alkyl according to the above definition that is modified by one or several fluoride groups F.
  • fluoro-substituted alkyl include -CH 2 F, -CHF 2 , -CF 3 , -(CH 2 ) 2 F, -(CHF) 2 H, -(CHF) 2 F, -C 2 F 5 , -(CH 2 ) 3 F, -(CHF) 3 H, -(CHF) 3 F, -C 3 F 7 , -(CH 2 ) 4 F, -(CHF) 4 H, -(CHF) 4 F and -C 4 F 9 .
  • Non-limiting examples of hydroxyl- and fluoro-substituted alkyl include -CHFCH 2 OH, - CF 2 CH 2 OH, -(CHF) 2 CH 2 OH, -(CF 2 ) 2 CH 2 OH, -(CHF) 3 CH 2 OH, -(CF 2 ) 3 CH 2 OH, -(CH 2 ) 3 OH, -CF 2 CH(OH)CH 3 , -CF 2 CH(OH)CF 3 , -CF(CH 2 OH)CHFCH 3 , and -CF(CH 2 OH)CHFCF 3 .
  • O-alkyl refers to an alkyloxy moiety (e.g. 0-CH 3 ) wherein the alkyl part is defined as above.
  • aryl in the context of the present specification signifies a cyclic aromatic C5-C10 hydrocarbon that may comprise a heteroatom (e.g. N, O, S).
  • heteroatom e.g. N, O, S.
  • aryl include, without being restricted to, phenyl and naphthyl, and any heteroaryl.
  • a heteroaryl is an aryl that comprises one or several nitrogen, oxygen and/or sulphur atoms.
  • heteroaryl include, without being restricted to, pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, oxazole, pyridine, pyrimidine, thiazin, quinoline, benzofuran and indole.
  • An aryl or a heteroaryl in the context of the specification additionally may be substituted by one or more alkyl groups.
  • a phenyl in the context of the present specification is a 6-membered aromatic carbon ring (C 6 H 6 ). Phenyl may be substituted be any substituent specified.
  • An aryl methylene in the context of the present specification signifies a CFh (-methylene) group substituted by an aryl moiety.
  • One non-limiting example of aryl methylene is a benzyl (Bn) group.
  • Bn benzyl
  • a heteroaryl methylene in the context of the present specification signifies a CFh (-methylene) group substituted by a heteroaryl moiety.
  • heteroaryl examples include, without being restricted to, pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, oxazole, pyridine, pyrimidine, thiazin, quinoline, benzofuran and indole.
  • An aryl or a heteroaryl in the context of this specification additionally may be substituted by one or more alkyl groups.
  • a carboxylic ester is a group -CO2R, with R being defined further in the description.
  • a carboxylic amide is a group -CONHR, with R being defined further in the description.
  • treating or treatment of any disease or disorder refers to ameliorating the disease or disorder (e.g. slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • treating or treatment refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • treating refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • Methods for assessing treatment and/or prevention of disease are generally known in the art, unless specifically described hereinbelow.
  • a first aspect of the invention relates to a compound characterized by a general formula (200)
  • R 4 is an unsubstituted or methyl-substituted 5- or 6-membered aryl or heteroaryl
  • R 5 is an unsubstituted or substituted aryl with the substituent being F, Cl, C1-C3 alkyl, C1-C3 alkyl ether, vinyl or allyl ether;
  • R 6 is COR c or CONHR c with R c being an unsubstituted or C1-C3 alkyl substituted heteroaryl.
  • the compound may be synthesised by a general route shown in scheme 1.
  • R 4 is selected from
  • R 5 is selected from
  • R 6 is selected from
  • the compound is characterized by a formula (201 )
  • the present invention also relates to a pharmaceutical composition comprising a compound according to this first aspect. It further relates to a compound according to this first aspect for its use as a drug.
  • a second aspect of the invention relates to a compound characterized by a general formula
  • R 1 is selected from
  • R 21 , R 22 , R 23 , R 22‘ , and R 21 are independently selected from H, halogen, unsubstituted C 1 -C 3 alkyl or O-alkyl, fluoro-substituted C 1 -C 3 alkyl or O-alkyl;
  • R 31 , R 32 , R 33 , R 32 ‘, and R 31 ’ are independently selected from H, F, Cl, CF 3 , methyl, ethyl, O-methyl, and O-CF 3 ;
  • R D is NH, N-methyl or O; or R 3 is NHR D orOR D , wherein R D is a 5- or 6-membered unsubstituted or amino-/hydroxy- or F-substituted cyclic alkyl.
  • the compound may be synthesised by a general route shown in scheme 2.
  • R 21 , R 22 , R 23 , R 22‘ , and R 21 are independently selected from H, F, Cl, methyl, CF 3 , ethyl, O-methyl, and O-CF 3 .
  • R 21 and R 22 ’ are independently selected from halogen, unsubstituted C 1 -C 3 alkyl or O-alkyl, fluoro-substituted C 1 -C 3 alkyl or O-alkyl and the other ones are H, or R 23 is selected from halogen, unsubstituted C 1 -C 3 alkyl or O-alkyl, fluoro-substituted C 1 -C 3 alkyl or O-alkyl and the other ones are H.
  • R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl.
  • R 2 is selected from
  • R 3 is selected from
  • the compound is characterized by a formula (101 )
  • the present invention also relates to a pharmaceutical composition comprising a compound according to this second aspect. It further relates to a compound according to this second aspect for its use as a drug.
  • a third aspect of the invention relates to the compound of to the first or second aspect for use for the treatment of an eating disorder, cachexia or anorexia, particularly anorexia nervosa, bulimia, cachexia associated with tumour disease, viral or bacterial infection; cachexia associated with a psychological disorder, particularly cachexia associated with stress, depression, or anxiety; cachexia associated with, particularly a gastrointestinal disorder selected from peptic ulcer, GERD, and ulcerative colitis; medication-induced anorexia associated with chemotherapy, administration of a laxative or amphetamine drug.
  • the compounds according to the first and second aspect increases the appetite.
  • the invention relates to the use of a compound according to this first or second aspect for the manufacture of a medicament for treating of an eating disorder, cachexia or anorexia, particularly anorexia nervosa, bulimia, cachexia associated with tumour disease, viral or bacterial infection; cachexia associated with a psychological disorder, particularly cachexia associated with stress, depression, or anxiety; cachexia associated with, particularly a gastrointestinal disorder selected from peptic ulcer, GERD, and ulcerative colitis; medication-induced anorexia associated with chemotherapy, administration of a laxative or amphetamine drug.
  • the invention relates to a method for increasing the appetite of a subject comprising administering a compound according to this first or second aspect to the subject. The method could be a non- therapeutic method.
  • the method could be a therapeutic method for treating an eating disorder, more particularly cachexia or anorexia, particularly anorexia nervosa, bulimia, cachexia associated with tumour disease, viral or bacterial infection; cachexia associated with a psychological disorder, particularly cachexia associated with stress, depression, or anxiety; cachexia associated with, particularly a gastrointestinal disorder selected from peptic ulcer, GERD, and ulcerative colitis; medication-induced anorexia associated with chemotherapy, administration of a laxative or amphetamine drug.
  • the compound of the first or second aspect of the invention is comprised in a foodstuff or food additive, particularly for use in animal farming.
  • a fourth aspect of the invention relates to a compound characterized by a general formula (300)
  • X is S, O or N-methyl
  • R 7 is H, F, Cl or C 1 -C 3 alkyl
  • R 8 is H, F, Cl or C 1 -C 3 alkyl
  • R 9 is NH2, NH-methyl, OH or methyl
  • R 101 , R 102 , R 103 , R 102 ‘, and R 101 ’ are independently selected from H, F, Cl, CF 3 , methyl, and NO2.
  • the compound may be synthesised by a general route shown in scheme 3.
  • X is selected from S, O, and N-methyl.
  • R 7 is selected from H and methyl.
  • R 8 is selected from H, Cl, and methyl.
  • R 9 is selected from NH2, NH-methyl, OH, methyl.
  • R 10 is selected from
  • the compound is characterized by a formula (302)
  • the present invention also relates to a pharmaceutical composition comprising a compound according to this fourth aspect. It further relates to a compound according to this fourth aspect for its use as a drug.
  • a fifth aspect of the invention relates to the compound of the fourth aspectfor use for the treatment of a disease selected from obesity, binge eating disorder, metabolic syndrome, prediabetes, type 2 diabetes, dyslipidaemia, hypertension, cardiovascular disease, non-alcoholic fatty liver disease, polycystic ovary syndrome, female infertility, male hypogonadism, obstructive sleep apnoea, asthma/reactive airway disease, osteoarthritis, urinary stress incontinence, gastroesophageal reflux disease, and depression.
  • a disease selected from obesity, binge eating disorder, metabolic syndrome, prediabetes, type 2 diabetes, dyslipidaemia, hypertension, cardiovascular disease, non-alcoholic fatty liver disease, polycystic ovary syndrome, female infertility, male hypogonadism, obstructive sleep apnoea, asthma/reactive airway disease, osteoarthritis, urinary stress incontinence, gastroesophageal reflux disease, and depression.
  • the invention also relates to the use of a compound of the fourth aspect for the manufacture of a medicament for the treatment of a disease selected from obesity, binge eating disorder, metabolic syndrome, prediabetes, type 2 diabetes, dyslipidaemia, hypertension, cardiovascular disease, non-alcoholic fatty liver disease, polycystic ovary syndrome, female infertility, male hypogonadism, obstructive sleep apnoea, asthma/reactive airway disease, osteoarthritis, urinary stress incontinence, gastroesophageal reflux disease, and depression.
  • a disease selected from obesity, binge eating disorder, metabolic syndrome, prediabetes, type 2 diabetes, dyslipidaemia, hypertension, cardiovascular disease, non-alcoholic fatty liver disease, polycystic ovary syndrome, female infertility, male hypogonadism, obstructive sleep apnoea, asthma/reactive airway disease, osteoarthritis, urinary stress incontinence, gastroesophageal reflux disease,
  • the invention relates to a method for decreasing the appetite in a subject comprising administering a compound of the fourth aspect.
  • the method is a non-therapeutic method.
  • the goal could be improved the physical appearance by reducing the weight.
  • the subject has a normal body mass index.
  • the method can have a therapeutic object, for instance for treating a disease selected from obesity, binge eating disorder, metabolic syndrome, prediabetes, type 2 diabetes, dyslipidaemia, hypertension, cardiovascular disease, non-alcoholic fatty liver disease, polycystic ovary syndrome, female infertility, male hypogonadism, obstructive sleep apnoea, asthma/reactive airway disease, osteoarthritis, urinary stress incontinence, gastroesophageal reflux disease, and depression.
  • a disease selected from obesity, binge eating disorder, metabolic syndrome, prediabetes, type 2 diabetes, dyslipidaemia, hypertension, cardiovascular disease, non-alcoholic fatty liver disease, polycystic ovary syndrome, female infertility, male hypogonadism, obstructive sleep apnoea, asthma/reactive airway disease, osteoarthritis, urinary stress incontinence, gastroesophageal reflux disease, and depression.
  • Item A1 A compound characterized by a general formula (200)
  • R 4 is an unsubstituted or methyl-substituted 5- or 6-membered aryl or heteroaryl
  • R 5 is an unsubstituted or substituted aryl with the substituent being F, Cl, C1-C3 alkyl, C1-C3 alkyl ether, vinyl or allyl ether;
  • R 6 is COR c or CONHR c with R c being an unsubstituted or C1-C3 alkyl substituted heteroaryl.
  • Item A2 The compound according to item B1 , wherein
  • R 5 is selected from 4-prop-2-eneoxyphenyl, 4-methoxyphenyl, 4-methylphenyl and 4- chlorophenyl.
  • Item A3 The compound according to item B1 , wherein
  • R 5 is selected from 4-prop-2-eneoxyphenyl, 4-methoxyphenyl, 4-methylphenyl and 4- chlorophenyl.
  • Item A4 The compound according to item B1 , wherein
  • R 5 is selected from 4-prop-2-eneoxyphenyl, 4-methoxyphenyl, 4-methylphenyl and 4- chlorophenyl.
  • Item A5 The compound according to item B1 , wherein
  • R 5 is selected from 4-prop-2-eneoxyphenyl, 4-methoxyphenyl, 4-methylphenyl and 4- chlorophenyl.
  • Item A6 The compound according to item B1 , wherein
  • R 5 is selected from 4-prop-2-eneoxyphenyl, 4-methoxyphenyl, 4-methylphenyl and 4- chlorophenyl.
  • Item A7 The compound according to item B1 , wherein
  • R 5 is selected from 4-prop-2-eneoxyphenyl, 4-methoxyphenyl, 4-methylphenyl and 4- chlorophenyl.
  • Item A8 The compound according to item B1 , wherein
  • R 5 is selected from 4-prop-2-eneoxyphenyl, 4-methoxyphenyl, 4-methylphenyl and 4- chlorophenyl.
  • Item A9 The compound according to item B1 , wherein
  • R 5 is selected from 4-prop-2-eneoxyphenyl, 4-methoxyphenyl, 4-methylphenyl and 4- chlorophenyl.
  • Item A10 The compound according to item B1 , wherein
  • R 5 is selected from 4-prop-2-eneoxyphenyl, 4-methoxyphenyl, 4-methylphenyl and 4- chlorophenyl.
  • Item A11 The compound according to item B1 , wherein
  • R 5 is selected from 4-prop-2-eneoxy phenyl, 4-methoxyphenyl, 4-methylphenyl and 4- chlorophenyl.
  • Item A12 The compound according to item B1 , wherein
  • R 5 is selected from 4-prop-2-eneoxyphenyl, 4-methoxyphenyl, 4-methylphenyl and 4- chlorophenyl.
  • Item A13 The compound according to item B1 , wherein
  • R 5 is selected from 4-prop-2-eneoxyphenyl, 4-methoxyphenyl, 4-methylphenyl and 4- chlorophenyl.
  • Item A14 The compound according to item B1 , wherein
  • R 5 is selected from 4-prop-2-eneoxyphenyl, 4-methoxyphenyl, 4-methylphenyl and 4- chlorophenyl.
  • Item A15 The compound according to item B1 , wherein
  • R 5 is selected from 4-prop-2-eneoxyphenyl, 4-methoxyphenyl, 4-methylphenyl and 4- chlorophenyl.
  • Item A16 The compound according to item B1 , wherein
  • R 5 is selected from 4-prop-2-eneoxyphenyl, 4-methoxyphenyl, 4-methylphenyl and 4- chlorophenyl.
  • Item A17 The compound according to item B1 , wherein
  • R 5 is selected from 4-prop-2-eneoxyphenyl, 4-methoxyphenyl, 4-methylphenyl and 4- chlorophenyl.
  • Item A18 The compound according to item B1 or B2, characterized by a formula (201 )
  • Item B1 A compound characterized by a general formula (100)
  • R 1 is selected from
  • R 21 , R 22 , R 23 , R 22‘ , and R 21 are independently selected from H, halogen, unsubstituted C 1 -C 3 alkyl or O-alkyl, fluoro-substituted C 1 -C 3 alkyl or O-alkyl, particularly R 21 , R 22 , R 23 , R 22‘ , and R 21’ are independently selected from H, F, Cl, methyl, CF 3 , ethyl, O-methyl, and O-CF 3 ; more particularly R 21 and R 22 ’ are independently selected from halogen, unsubstituted C 1 -C 3 alkyl or O- alkyl, fluoro-substituted C 1 -C 3 alkyl or O-alkyl and the other ones are H, or R 23 is selected from halogen, unsubstituted C 1 -C 3 alkyl or O-alkyl, fluoro- substituted C 1 -C 3 alkyl or O
  • R 31 , R 32 , R 33 , R 32 ‘, and R 31 ’ are independently selected from H, F, Cl, CF 3 , methyl, ethyl, O-methyl, and O-CF 3 ;
  • D is NH, N-methyl or O
  • R 3 is NHR D orOR D , wherein R D is a 5- or 6-membered unsubstituted or amino-/hydroxy- or F-substituted cyclic alkyl.
  • Item B2 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso- butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 2-methoxy-5-fluorophenyl and R 3 is phenylamidyl.
  • Item B3 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso- butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 2-methoxy-5-fluorophenyl and R 3 is
  • Item B4 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 2-methoxy-5-fluorophenyl and R 3 is 3-chlorophenylamidyl.
  • Item B5 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso- butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 2-methoxy-5-fluorophenyl and R 3 is 2- methoxy-5-methylphenylamidyl.
  • Item B6 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso- butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 2-methoxy-5-fluorophenyl and R 3 is
  • Item B7 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso- butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 3-chloro-6-methylphenyl and R 3 is phenylamidyl.
  • Item B8 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso- butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 3-chloro-6-methylphenyl and R 3 is 2,5- dimethylphenylamidyl.
  • Item B9 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 3-chloro-6-methylphenyl and R 3 is 3-chlorophenylamidyl.
  • Item B10 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 3-chloro-6-methylphenyl and R 3 is 2-methoxy-5-methylphenylamidyl.
  • Item B1 1 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 3-chloro-6-methylphenyl and R 3 is 2,5-dimethylphenyloxyl.
  • Item B12 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 3-chloro-6-methoxyphenyl and R 3 is phenylamidyl.
  • Item B13 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 3-chloro-6-methoxyphenyl and R 3 is 2,5-dimethylphenylamidyl.
  • Item B14 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 3-chloro-6-methoxyphenyl and R 3 is 3-chlorophenylamidyl.
  • Item B15 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 3-chloro-6-methoxyphenyl and R 3 is 2-methoxy-5-methylphenylamidyl.
  • Item B16 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 3-chloro-6-methoxyphenyl and R 3 is 2,5-dimethylphenyloxyl.
  • Item B17 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 4-methoxyphenyl and R 3 is phenylamidyl.
  • Item B18 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 4-methoxyphenyl and R 3 is 2,5- dimethylphenylamidyl.
  • Item B19 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 4-methoxyphenyl and R 3 is 3- chlorophenylamidyl.
  • Item B20 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 4-methoxyphenyl and R 3 is 2- methoxy-5-methylphenylamidyl.
  • Item B21 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 4-methoxyphenyl and R 3 is 2,5- dimethylphenyloxyl.
  • Item B22 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 2-trifluoromethoxyphenyl and R 3 is phenylamidyl.
  • Item B23 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 2-trifluoromethoxyphenyl and R 3 is
  • Item B24 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 2-trifluoromethoxyphenyl and R 3 is 3-chlorophenylamidyl.
  • Item B25 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 2-trifluoromethoxyphenyl and R 3 is 2-methoxy-5-methylphenylamidyl.
  • Item B26 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 2-trifluoromethoxyphenyl and R 3 is
  • Item B27 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 2-chloro-5-methoxyphenyl and R 3 is phenylamidyl.
  • Item B28 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 2-chloro-5-methoxyphenyl and R 3 is 2,5-dimethylphenylamidyl.
  • Item B29 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 2-chloro-5-methoxyphenyl and R 3 is 3-chlorophenylamidyl.
  • Item B30 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 2-chloro-5-methoxyphenyl and R 3 is 2-methoxy-5-methylphenylamidyl.
  • Item B31 The compound according to item A1 , wherein R 1 is selected from methyl, n-propyl, iso-butyl, phenyl, 4-methylphenyl, and N-dimethyl; and R 2 is 2-chloro-5-methoxyphenyl and R 3 is 2,5-dimethylphenyloxyl.
  • Item B32 The compound according to item A1 or A28, characterized by a formula (101 )
  • Item AB1 The compound according to any one of items A1 through B18 for treatment of an eating disorder, cachexia or anorexia, particularly anorexia nervosa, bulimia, cachexia associated with tumour disease, viral or bacterial infection; cachexia associated with a psychological disorder, particularly cachexia associated with stress, depression, or anxiety; cachexia associated with, particularly a gastrointestinal disorder selected from peptic ulcer, GERD, and ulcerative colitis; medication-induced anorexia associated with chemotherapy, administration of a laxative or amphetamine drug.
  • an eating disorder cachexia or anorexia, particularly anorexia nervosa, bulimia, cachexia associated with tumour disease, viral or bacterial infection
  • cachexia associated with a psychological disorder particularly cachexia associated with stress, depression, or anxiety
  • cachexia associated with particularly a gastrointestinal disorder selected from peptic ulcer, GERD, and ulcerative colitis
  • medication-induced anorexia associated with chemotherapy administration of a laxative or amphetamine drug.
  • Item AB2 A foodstuff or food additive comprising a compound according to any one of items A1 through B18, particularly for use in animal farming.
  • Item C1 A compound characterized by a general formula (300)
  • - X is S, O or N-methyl
  • R 7 is H, F, Cl or C1-C3 alkyl
  • R 8 is H, F, Cl or C1-C3 alkyl
  • R 9 is NH2, NH-methyl, OH or methyl
  • R 101 , R 102 , R 103 , R 102 ‘, and R 101 ’ are independently selected from H, F, Cl, CF3, methyl, and NO2.
  • Item C2 The compound according to item C1 , wherein
  • - X is selected from S, O, and N-methyl
  • R 7 is selected from H and methyl
  • R 8 is selected from H, Cl, and methyl
  • R 9 is selected from NH2, NH-methyl, OH, methyl;
  • R 10 is selected from
  • Item C3 The compound according to item C1, wherein X is S; R 7 is H; R 8 is H; R 9 is NH ; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4-fluorophenyl, and 3-nitrophenyl.
  • Item C4 The compound according to item C1, wherein X is O; R 7 is H; R 8 is H; R 9 is NH ;and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4-fluorophenyl, and 3-nitrophenyl.
  • Item C5 The compound according to item C1, wherein X is N-methyl; R 7 is H; R 8 is H; R 9 is NH ;and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C6 The compound according to item C1, wherein X is S; R 7 is methyl; R 8 is H; R 9 is NH ;and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C7 The compound according to item C1, wherein X is O; R 7 is methyl; R 8 is H; R 9 is NH ;and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C8 The compound according to item C1, wherein X is N-methyl; R 7 is methyl; R 8 is H; R 9 is NH ;and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C9 The compound according to item C1 , wherein X is S; R 7 is H; R 8 is Cl; R 9 is NH 2 ;and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4-fluorophenyl, and 3-nitrophenyl.
  • Item C10 The compound according to item C1 , wherein X is O; R 7 is H; R 8 is Cl; R 9 is NH 2 ; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4-fluorophenyl, and 3-nitrophenyl.
  • Item C1 1 The compound according to item C1 , wherein X is N-methyl; R 7 is H; R 8 is Cl; R 9 is NH 2 ;and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C12 The compound according to item C1 , wherein X is S; R 7 is methyl; R 8 is Cl; R 9 is NH 2 ; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C13 The compound according to item C1 , wherein X is O; R 7 is methyl; R 8 is Cl; R 9 is NH 2 ; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C14 The compound according to item C1 , wherein X is N-methyl; R 7 is methyl; R 8 is Cl; R 9 is NH 2 ; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C15 The compound according to item C1 , wherein X is S; R 7 is H; R 8 is methyl; R 9 is NH 2 ; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C16 The compound according to item C1 , wherein X is O; R 7 is H; R 8 is methyl; R 9 is NH 2 ;and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C17 The compound according to item C1 , wherein X is N-methyl; R 7 is H; R 8 is methyl; R 9 is NH 2 ; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C18 The compound according to item C1 , wherein X is S; R 7 is methyl; R 8 is methyl; R 9 is NH 2 ; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C19 The compound according to item C1 , wherein X is O; R 7 is methyl; R 8 is methyl; R 9 is NH 2 ; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C20 The compound according to item C1 , wherein X is N-methyl; R 7 is methyl; R 8 is methyl; R 9 is NH 2 ; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2- chloro,4-fluorophenyl, and 3-nitrophenyl.
  • Item C21 The compound according to item C1 , wherein X is S; R 7 is H; R 8 is H; R 9 is NH- methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C22 The compound according to item C1 , wherein X is O; R 7 is H; R 8 is H; R 9 is NH- methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C23 The compound according to item C1 , wherein X is N-methyl; R 7 is H; R 8 is H; R 9 is NH-methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C24 The compound according to item C1 , wherein X is S; R 7 is methyl; R 8 is H; R 9 is NH- methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C25 The compound according to item C1 , wherein X is O; R 7 is methyl; R 8 is H; R 9 is NH- methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C26 The compound according to item C1 , wherein X is N-methyl; R 7 is methyl; R 8 is H; R 9 is NH-methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2- chloro,4-fluorophenyl, and 3-nitrophenyl.
  • Item C27 The compound according to item C1 , wherein X is S; R 7 is H; R 8 is methyl; R 9 is NH- methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C28 The compound according to item C1 , wherein X is O; R 7 is H; R 8 is methyl; R 9 is NH- methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C29 The compound according to item C1 , wherein X is N-methyl; R 7 is H; R 8 is methyl; R 9 is NH-methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2- chloro,4-fluorophenyl, and 3-nitrophenyl.
  • Item C30 The compound according to item C1 , wherein X is S; R 7 is methyl; R 8 is methyl; R 9 is NH-methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C31 The compound according to item C1 , wherein X is O; R 7 is methyl; R 8 is methyl; R 9 is NH-methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C32 The compound according to item C1 , wherein X is N-methyl; R 7 is methyl; R 8 is methyl; R 9 is NH-methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4-fluorophenyl, and 3-nitrophenyl.
  • Item C33 The compound according to item C1 , wherein X is S; R 7 is H; R 8 is H; R 9 is OH; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4-fluorophenyl, and 3-nitrophenyl.
  • Item C34 The compound according to item C1 , wherein X is O; R 7 is H; R 8 is H; R 9 is OH; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4-fluorophenyl, and 3-nitrophenyl.
  • Item C35 The compound according to item C1 , wherein X is N-methyl; R 7 is H; R 8 is H; R 9 is OH; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C36 The compound according to item C1 , wherein X is S; R 7 is methyl; R 8 is H; R 9 is OH; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C37 The compound according to item C1 , wherein X is O; R 7 is methyl; R 8 is H; R 9 is OH; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C38 The compound according to item C1 , wherein X is N-methyl; R 7 is methyl; R 8 is H; R 9 is OH; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C39 The compound according to item C1 , wherein X is S; R 7 is H; R 8 is methyl; R 9 is OH; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C40 The compound according to item C1 , wherein X is O; R 7 is H; R 8 is methyl; R 9 is OH; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C41 The compound according to item C1 , wherein X is N-methyl; R 7 is H; R 8 is methyl; R 9 is OH; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C42 The compound according to item C1 , wherein X is S; R 7 is methyl; R 8 is methyl; R 9 is OH; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C43 The compound according to item C1 , wherein X is O; R 7 is methyl; R 8 is methyl; R 9 is OH; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C44 The compound according to item C1 , wherein X is N-methyl; R 7 is methyl; R 8 is methyl; R 9 is OH; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2- chloro,4-fluorophenyl, and 3-nitrophenyl.
  • Item C45 The compound according to item C1 , wherein X is S; R 7 is H; R 8 is H; R 9 is methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C46 The compound according to item C1 , wherein X is O; R 7 is H; R 8 is H; R 9 is methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C47 The compound according to item C1 , wherein X is N-methyl; R 7 is H; R 8 is H; R 9 is methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C48 The compound according to item C1 , wherein X is S; R 7 is methyl; R 8 is H; R 9 is methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C49 The compound according to item C1 , wherein X is O; R 7 is methyl; R 8 is H; R 9 is methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C50 The compound according to item C1 , wherein X is N-methyl; R 7 is methyl; R 8 is H; R 9 is methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C51 The compound according to item C1 , wherein X is S; R 7 is H; R 8 is methyl; R 9 is methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C52 The compound according to item C1 , wherein X is O; R 7 is H; R 8 is methyl; R 9 is methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C53 The compound according to item C1 , wherein X is N-methyl; R 7 is H; R 8 is methyl; R 9 is methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C54 The compound according to item C1 , wherein X is S; R 7 is methyl; R 8 is methyl; R 9 is methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C55 The compound according to item C1 , wherein X is O; R 7 is methyl; R 8 is methyl; R 9 is methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4- fluorophenyl, and 3-nitrophenyl.
  • Item C56 The compound according to item C1 , wherein X is N-methyl; R 7 is methyl; R 8 is methyl; R 9 is methyl; and R 10 is selected from 4-nitrophenyl, 4-trifluoromethyl, 4- chlorophenyl, 2-chloro,4-fluorophenyl, and 3-nitrophenyl.
  • Item C57 The compound according to item C1 or C2, characterized by a formula (302)
  • Item C58 The compound according to any one of the items C1 through C57 for treatment of a disease selected from obesity, binge eating disorder, metabolic syndrome, prediabeles, type 2 diabetes, dyslipidaemia, hypertension, cardiovascular disease, non-alcoholic fatty liver disease, polycystic ovary syndrome, female infertility, male hypogonadism, obstructive sleep apnoea, asthma/reactive airway disease, osteoarthritis, urinary stress incontinence, gastroesophageal reflux disease, and depression.
  • a disease selected from obesity, binge eating disorder, metabolic syndrome, prediabeles, type 2 diabetes, dyslipidaemia, hypertension, cardiovascular disease, non-alcoholic fatty liver disease, polycystic ovary syndrome, female infertility, male hypogonadism, obstructive sleep apnoea, asthma/reactive airway disease, osteoarthritis, urinary stress incontinence, gastroesophageal reflux disease, and depression
  • any specifically mentioned drug may be present as a pharmaceutically acceptable salt of said drug.
  • Pharmaceutically acceptable salts comprise the ionized drug and an oppositely charged counterion.
  • Non-limiting examples of pharmaceutically acceptable anionic salt forms include acetate, benzoate, besylate, bitatrate, bromide, carbonate, chloride, citrate, edetate, edisylate, embonate, estolate, fumarate, gluceptate, gluconate, hydrobromide, hydrochloride, iodide, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl sulfate, mucate, napsylate, nitrate, pamoate, phosphate, diphosphate, salicylate, disalicylate, stearate, succinate, sulfate, tartrate, tosylate, triethiodide and valerate.
  • Fig. 1 Homeostatic state modulates feeding behavior, but not spontaneous activity, arousal to visual or acoustic signals nor habituation in zebrafish larvae.
  • A Zebrafish larvae were raised under controlled conditions until 7 dpf, loaded into a well of a 96-well plate and fasted for different time-periods prior assessment of distinct behaviors.
  • B A custom-built imaging platform can quantify larval feeding behavior by measuring intestinal food content if combined with feeding fluorescently labeled live prey; larval locomotion by tracking swimming behavior; larval arousal by presenting visual and acoustic signals; and larval habituation (non- associative learning) by repeatedly presenting inconsequential stimuli.
  • the two exemplary images show data quality used for larval activity tracking and larval intestinal food content quantification using two distinct invisible light sources. All measurements were acquired under daylight conditions, scale bar - 1 mm.
  • C After different fasting periods, larvae were given access to fluorescently labeled paramecia and their intestinal food content quantified for 2 hours.
  • D total food intake
  • E initial intake rate
  • F digestion rate
  • (G) Simultaneously, larval locomotor activity was tracked for 2 hours, n 48, lc - line crosses.
  • (H) Larval zebrafish react to dark flashes with increased motor output. After different fasting periods, larvae were exposed to eight dark flashes (750ms duration, inter-stimuli interval 30s) and their locomotion quantified. The triggered average is shown, n 48.
  • (I) An acoustic stimulus triggers larval locomotion. Identical experiment as in H, but here a single tap was presented instead of a dark flash, n 48.
  • Fig. 2 Available appetite modulators trigger a pleiotropy of behaviors.
  • A Schematic of multi-behavior protocol used to test drug impact. Briefly, 2h fasted larvae were pre-exposed to a drug for 30 min prior multi-behavioral profiling. Here, the inventors tested many appetite modulating drugs used in humans. Each drug’s behavioral impact was condensed into a single, quantitative behavioral barcode, which is illustrated here for two classic anorectic drugs - nicotine and rimonabant - in detail, n>12.
  • B After giving access to live prey, the inventors quantified larvae’s intestinal food content for 2 h and condensed the fluorescent traces into two feeding periods (F1 , F2).
  • Each square represents an SSMD value (red, higher; blue, lower than control) for a single behavioral metric and jointly they form a compounds behavioral barcode.
  • the black box indicates the barcodes for nicotine and rimonabant, shown in detail in panel B-J, orange box is feeding behavior, green box - habituation; * barcodes shown for drugs tested at 100 mM.
  • pharmacology represent chemical structures with unknown biological activity.
  • Behavioral metrics F, feeding; S, spontaneous activity; V, visual response; A, acoustic response; H, habituation; L, lethargy; 1 or 2, different time periods.
  • Fig. 3 Diversity of drug-induced behavioral changes.
  • A Hierarchical clustering groups hit compounds with similar behavioral barcodes based on their correlation.
  • Dendrogram color code localizes selective clusters shown at higher magnification.
  • B tSNE groups hit compounds with similar barcodes using non-linear probability distributions and preserves local distance metrics. All 4,801 hits are shown in a two-dimensional space. The tSNE map is false-colored with the primary behavior modulated for a given compound. The magnification of the rectangle is shown in panel (C).
  • C tSNE map location of selected hierarchical clusters magnified in panel A.
  • E Histogram of the pairwise Pearson correlation ( R ) for compound barcodes sharing one or more targets, or compound barcodes with unknown target (two-tailed, two-sample Kolmogorov- Smirnov test, line depicts median).
  • Tanimoto coefficient >0.85 reflects very similar structures.
  • Fig. 4 Identification of novel and selective appetite modulators.
  • A Barcodes of all hits modulating feeding behavior selectively based on the SSMD threshold sorted by their effect size on feeding period 1 (F1 ).
  • B 27 structurally novel compounds were selected based on the displayed behavioral barcodes and unique chemical structures. All compounds were validated and the complete validation data is shown in Fig. 5.
  • C Heatmap illustration of in vitro target binding profiles for all 27 compounds across 43 different human targets. All binding assays were validated with a positive control.
  • adrenergic receptors a-1A, a-1 B, a-1 D, a-2A, a-2B, b- 1 , b-2; dopamine receptors, D1-D5; gamma- amino butyric acid (GABA)-A receptor, peripheral benzodiazepine receptor (PBR), allosteric benzodiazepine binding site on rat brain slices (BZP); histamine receptors, H1 , H3, H4; muscarinic receptors, M1-M5; serotonin receptors (5- hydroxytryptamine, 5-HT), 1A, 1 B, 1 D, 1 E, 2A, 2B, 2C, 3, 5A, 6, 7; sigma receptors 1 , 2; opioid receptors, d-opioid receptor (DOR), k-opioid receptor (KOR), m-opioid receptors (MOR);
  • DOR d-opioid receptor
  • KOR k-opio
  • biogenic amine transporters dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT).
  • DAT dopamine transporter
  • NET norepinephrine transporter
  • SERT serotonin transporter
  • Fig. 7 Orexigenic and anorectic candidate compound impact on mice behaviors.
  • Fig. 8 Spectra of candidate compounds.
  • A spectrum oC compound A.
  • B spectrum oC compound B.
  • C spectrum aC compound C.
  • Larvae from bucket crosses were collected and pooled in blue water (density of >5 ml / larvae, pH 7.2 - sodium bicarbonate buffer, 1 g/l methylene blue, 0.2 g/l instant ocean salt). Live embryos were selected ⁇ 24 hpf and transferred to the automated growth system in 2 L tanks.
  • the automated system was maintained at 28 °C and at a 14:10 h lighhdark cycle.
  • Protozoan pellets (Carolina Biological Supply, Burlington, USA) were dissolved in boiling larval growth water. After cooling, live paramecia and RotiGrow Plus (Reed Mariculture, Campbell, USA) were added to the protozoan water and the culture incubated for a minimum of 2 days at 28 °C prior to use. All paramecia strains were cultured using this protocol and were originally obtained from Ward’s science (Rochester, USA). Visual inspection of paramecia size and structure enabled to distinguish between paramecium caudatum, paramecium bursaria or bdelloidea. If not stated differently, paramecium caudatum was used for all experiments. All paramecia cultures were visually inspected for purity prior to use with light microscopy.
  • Fluorescent excitation light was generated using a single, cooled 740 nm led (LZ4, LED engine), a lens (12° uniform spot, LED engine) and a squared light diffuser (Thorlabs, Newton, USA).
  • the new generation of IDS camera was used with significantly improved sensitivity in the inventors’ hands in the 780-820 nm range [emission range of fluorophore] (IDS UI-3370CP-NIR, IDS, Obersulm, Germany).
  • a push-tap solenoid (Guardian Electric 28P-I-12D, Allied Electronis, Texas, USA) enables to deliver acoustic stimuli. Four instruments were constructed to enable higher throughput.
  • Emission light calibration was conducted using DiR dye (Molecular Probes, Eugene, USA) dissolved in DMSO at different concentrations, and recording fluorescent emission from the same probes for 100 ms on all the different behavioral imaging platforms. All image platforms showed very similar sensitivity for fluorescence detection.
  • larval zebrafish were transferred to a single well of a flat-bottom 96 well plate (Falcon, VWR, USA) in 150 mI larval growth water. Within 1 min prior to starting behavioral imaging, 50 mI of labeled paramecia culture (OD 4 90nm > 0.5, >500 paramecia/well; see Jordi et al. (Jordi et al.
  • larvae were pre-exposed to 30 mI of compounds (final concentration 10 mM in 0.15 % dimethyl sulfoxide, if not stated differently) for 30 min.
  • 50 mI of labeled paramecia culture (OD 4 90nm > 0.5, >500 paramecia/well) were added, the plate transferred to the behavioral imaging platform and the experiment initialized.
  • the following compound libraries were tested: DIVERSetE library (ChemBridge, San Diego, USA, > 95% purity); Spectrum library (Microsource Discovery Systems, Gaylordsvill, USA, >95 % purity); Prestwick library (Prestwick Chemical, lllkirch, France, >95 % purity);
  • Biomol Neurotransmitter Library (BML-2810, ENZO Life Sciences, Farmingdale, USA, >95% purity). Individual compounds were re-ordered from suppliers. For the screen, each compound was tested in 6 animals. A subset of 530 compounds was tested in 12 or 18 animals because identical compounds were contained in multiple libraries. Lorcaserin (AdooQ Bioscience LLC, CA, USA), rimonabant-HCI (Sigma-aldrich, MO, USA) and anamorelin (AdooQ) were acquired at >98% purity.
  • the experimental flow is graphically depicted in Fig. 2A.
  • the inventors collected a fluorescent image, required to measure intestinal paramecia content, with 100 ms exposure time every min for 2 h; and simultaneously use transmitted IR images to track in real time spontaneous swimming activity of all zebrafish larvae at a camera frame rate of 10 Hz.
  • 8 dark flashes 750 ms, inter-stimulus interval [ISI] 30 s
  • 8 taps ISI 30 s
  • Larval intestines were identified using intensity and size thresholds. Such thresholding led to a number of particles per well, which were sorted by signal strength (area * mean intensity) and the top two stored as intestinal traces.
  • Kinematic traces were quantified as described in Kokel et al., where the number of times an animal crosses any of three parallel imaginary lines are counted (Kokel et al. Nature Chemical Biology 6, 231-237, (2010).). The inventors counted larval line crosses for each well at a frame rate of 10 Hz.
  • the data was pre-processed as follows on a well by well basis (Fig. 2): The fluorescence measurements were binned down to two-time periods reflecting the accumulated fluorescence in the first 40 min (F1 , feeding period 1 ) and the last 80 min of the experiment (F2, feeding period 2), respectively. Concurrent larval locomotion activity was condensed into one bin for the entire 2 h (S, spontaneous locomotion).
  • the inventors aligned the repeats of the initial eight dark flashes, the eight taps, and the four post-dark flashes to construct triggered- averages, each 28 s in length, using an interpolation-based alignment method to generate a standard time base.
  • SSMD Strictly Standardized Median Difference
  • Fertilized embroys were collected following natural spawning, visually inspected and three healthy randomly-selected embryo’s placed into a well of standard flat-bottom 6-well plate (VWR) filled with larvae’s growth water. Each well was treated either with DMSO, candidate compound A to D (10 mM) or EtOH (350 mM) one-hour post-fertilization. 6-well plates were maintained on a 14:10 h lighhdark cycle at 28°C. Every 12 hours each embryo was inspected with a stereomicroscope and scored for survival till 6 dpf. At 5 dpf, images were acquired with a stereomicroscope and body length measured using ImageJ.
  • the phototaxis experiment was executed identically to the thigmotaxis assay. The main difference being that one half of the well was covered with an infrared light proof shelter (no visible light passes, McMaster, New Jersey, USA). For data analysis, each well was split into 2 equal sized areas - shelter and open space. The time periods each fish spent in an area based on its coordinates were summed and the phototaxis index calculated as follows: [Time(open space)-Time(shelter)]/Time(total).
  • One agar pad (2 % agar in larvae’s growth water) contained mustard oil (noxious stimuli, 20 % (v/v) Allyl isothiocyanate, Sigma) and the other contained no additives.
  • mice 4-month-old male C57BL/6J mice (Charles River, Sulzfeld, Germany) were individually housed in wire-mesh hanging cages or in standard mice cages at a room temperature of 21 ⁇ 1 °C and an artificial 12/12 h light/dark cycle. Animals were able to see, hear and smell their conspecifics in neighboring cages and were not socially isolated. Water, food (mice chow-3436, Kliba Nafag, Kaiseraugst, Switzerland) and bedding was provided ad libitum, if not indicated differently. All procedures for mice handling and experimental interventions were according to Swiss Animal Welfare laws, approved by the“Kantonales Veterinaramt Zurich” and conform to the principles of UK regulations. Animals were adapted to novel housing situation and feeding schedule at least for 1 week. All experiments were conducted three times with saline injections prior to drug administration to habituate the animals to the experimental procedure.
  • mice received a tail cut for immediate blood glucose measurement (Breeze 2, Bayer AG, Leverkusen, Germany). Subsequently, candidate compounds were injected
  • mice were returned to their home cage for 30 min before a second blood glucose measurement was performed as described before.
  • mice displacement was tracked online at 16 Hz by a camera (Logitech C930e HD) positioned above the chamber which was illuminated with an infrared light source from below. The camera had an infrared filter mounted to avoid interference from visible light.
  • the tracking algorithm subtracted a 10- frames running-average background image, applied a size threshold to identify the mouse (min. motion detected was 5 mm) and extracted its coordinates. Extracted coordinates with linked timestamps were used to calculate displacement. Mice behavior was recorded for 15 min in complete darkness and the final 10 min were analyzed.
  • mice 3 h fasted mice were injected intraperitoneally with a candidate compound and were tracked in complete darkness 30 min post-injection as outlined above. After recording undisturbed behavior for 15 min, eight taps (75-85 Db) were applied to the mouse cage with an inter- stimulus interval of 30 s. The inventors aligned the repeats of the eight taps to a triggered- average using an interpolation-based alignment method to generate a standard time base. These time traces were normalized to the period preceding a given stimulus (2 s) to account for differences in spontaneous locomotion and the tap response index calculated as follows:
  • mice to white light flashes were tested similarly to the tap-response. Instead of taps, eight periods of 5 s white light flashes (300 lux, UV, and IR light filtered) were repeated every 30 s. The flash response index was calculated as follows: median displacement (time period of light) / median displacement (time period of darkness).
  • mice 3 h fasted mice were injected intraperitoneally with a candidate compound and were tracked in complete darkness 30 min post-injection with the apparatus outlined above.
  • the cage was split into 2 equal sized areas - border and center square. The time periods that each mouse spent in an area based on its coordinates were summed and the thigmotaxis index calculated as follows: [Time(wall) - Time(center)] / Time(total).
  • Powdered KOH (2.9 g, 51.3 mmol) was added to a suspension of 4,6-dimethyl-2-thioxo-1 ,2- dihydropyridine-3-carbonitrile (2.8 g, 17.1 mmol) and 2-bromo-4’-nitroacetophenone (4.2 g, 17.1 mmol) in anhydrous EtOH (100 ml).
  • the resulting thick suspension was stirred at room temperature for 6 h.
  • the suspension was concentrated to half volume and diluted with ethyl acetate. The mixture was filtered and the filtrate washed with concentrated citric acid (3x100ml), water (100 ml) and brine (100 ml).
  • Fig. 1A Prior to behavioral phenotyping at 7 days-post-fertilization (dpf), larvae were fasted for different time periods and placed into a 96-well plate. Subsequently, a custom-built imaging platform detected several distinct behavioral phenotypes in all 96 animals simultaneously (Fig.
  • FIG. 1 B first, larval zebrafish hunt and ingest live paramecia, a unicellular protozoan roughly 100 pm size, and thereby enable the quantitative characterization of feeding behavior.
  • the inventors fluorescently-labeled the prey and the imaging platform quantified larval food intake by detecting intestinal fluorescence content for 2 hours (Fig. 1 C).
  • Biologically grounded curve-fitting algorithms enabled the inventors to extract key characteristics of feeding behavior, namely total food intake, initial intake rate and digestion rate. Different fasting periods modulated these parameters analogous to observation in adult rodents and humans (Fig. 1 D-F).
  • the inventors simultaneously tracked larval locomotion to quantify their swimming activity for 2 hours (Fig. 1 B, G).
  • Example 2 Current appetite modulators are not selective for feeding behavior
  • Fig. 2G responsiveness to visual
  • Fig. 2H acoustic stimuli
  • Fig. 2I habituation
  • Fig. 2J lethargy
  • Nicotine and rimonabant both significantly reduced food intake (Fig. 2B-E). Additional nutritional and endocrinal interventions were previously demonstrated to have an analogous impact on feeding behavior in fish, rodents, and humans.
  • nicotine increased spontaneous activity, yet had no significant impact on any other tested behaviors (Fig. 2F-J).
  • Rimonabant decreased spontaneous activity, reduced the habituation response and modulated lethargy, but had no impact on the response to visual stimuli (Fig. 2F-J).
  • Example 3 Multi-behavioral profiles link compounds to their molecular mechanism of action independent of the underlying chemical structure
  • the inventors ought to screen for ideal psychoactive small molecules, that is, compounds which induce only their intended, single behavioral change. To that end, the inventors performed a high-throughput chemical screen to identify such putative selective bioactive compounds.
  • the inventors acquired quantitative multi-behavioral barcodes for a total of 10,421 compounds, each individually tested in at least 6 animals (Fig. 2L-M).
  • the inventors found two compounds with an unknown mechanism of action that had a strong correlation with known drugs targeting either histamine receptor 1 (H1 ), or muscarinic acetylcholine receptor 3 (M3), respectively (Fig. 3F-H). This behavioral phenotype correlation suggested a shared mechanism.
  • H1 histamine receptor 1
  • M3 muscarinic acetylcholine receptor 3
  • Fig. 3I-J In vitro competitive binding assays confirmed an interaction of these two unknown compounds with the H1 or M3 receptor, respectively.
  • the inventors identified two novel molecules binding human H1 and M3 receptor with nanomolar affinity in vitro as well as an in vivo behavioral phenotype.
  • the measured binding affinities are in the nanomolar range, which is at least one order of magnitudes stronger compared to compounds normally identified by in vitro targeted high-throughput screens (mM - mM range, see also Fig. 4C).
  • a compound’s molecular target is a predictor for its multi- behavioral impact in vivo.
  • Example 4 ⁇ The zebrafish central nervous system controls different behaviors by an
  • Example 5 Novel appetite modulators are potent and selective for feeding behavior and the majority is mechanistically independent of the main neurotransmitter systems
  • the hit rate for selective orexigenic compounds was 1.8 % and for selective anorectic compounds 0.7 %. Consequently, the selectivity filter reduced the hit rate by roughly 50% illustrating one advantage.
  • the inventors selected, after inspection of the individual barcodes and the chemistry, eleven orexigenic and eleven anorectic candidate compounds with unique chemical structures for validation (Fig. 4B).
  • Fig. 4C in vitro competitive binding assays
  • Fig. 4C a few candidate compounds bound with nanomolar affinity to targets that are established regulators of feeding behavior in mammals (histamine receptor 1 , serotonin receptor 2B or C [5-HT2B, 5-HT2C] and peripheral benzodiazepine receptor [PBR]), thereby independently validating our discovery strategy.
  • Example 6 Orexigenic and anorectic candidate compounds enable the selective control of appetite in zebrafish and mice
  • Fig. 5A Orexigenic candidate (oC) compound A and B doubled food intake, whereas the two anorectic candidate (aC) compounds C and D reduced food intake by more than 50 % in zebrafish (Fig. 5B-E, routes of synthesis shown in scheme 1-3, spectra shown in Fig. 8). None of the candidate compounds modulated the responsiveness to visual (Fig. 5F) or acoustic stimuli (Fig. 5G), spontaneous activity (Fig. 5H), habituation (Fig. 5I) and lethargy (Fig. 5J).
  • aC compound D bound to PBR, 5-HT2B and 5-HT2C receptor with nanomolar affinity (Fig. 5K, L), whereas the other candidate small molecules did not bind any of the 43 human neuronal targets with a millimolar affinity (Fig. 4C).
  • Norfenfluramine the active metabolite of the former anti- obesity drug fenfluramine, binds 5-HT2B and 5-HT2C receptor with similar affinities as aC D.
  • 5- HT2C receptor activity is considered the driver for fenfluramine’s anorectic effect and is the primary target of the recently approved anti-obesity agent lorcaserin.
  • the inventors monitored zebrafish development under the exposure of candidate drugs in vivo using light microscopy from the single fertilized cell- stage to the 6-dpf behaving larvae. None of the candidates had a significant impact on embryological mortality, developmental defects or temporal delays nor on the body length at 5 dpf, whereas EtOH exposure significantly reduced survival after hatching and lead to lordosis as reported previously (Fig. 5M, N). As the inventors were unable to detect an impact of the candidate compounds on normal vertebrate development, they tested for a drug impact on more subtle behavioral characteristics. These behaviors required the analysis of single fish at high temporal and spatial resolution and therefore are non-suitable for high-throughput screening.
  • thigmotaxis (or“wall-loving”), which is a validated behavioral index for anxiety in animals.
  • Anxiolytic drugs reduce thigmotaxis, whereas anxiogenic compounds enhance it in zebrafish larvae.
  • Candidate compound A-D did not modulate the thigmotaxic response in daylight compared to vehicle control nor did they interfere with the characteristic reduction of thigmotaxis observed with the onset of darkness (Fig. 50).
  • the inventors assessed the impact of the candidate compounds on two sensitive visual behaviors - phototaxis and the optomotor response. Larval zebrafish are attracted by light and averse to darkness, hence, perform positive phototaxis.
  • the optomotor response is an orienting behavior evoked by visual motion.
  • a closed loop setup presented a grating moving perpendicular to the body axes of an individual zebrafish.
  • the stimulus elicits a turning behavior within the direction of the stimulus.
  • the inventors did not detect a significant impact of candidate compounds on the correct execution nor the turn-angle used during the optomotor response (Fig. 5Q).
  • Larvae avoided the presence of noxious stimuli (here, mustard oil), but had no preference if presented a non-noxious stimulus (agar). This preference was not visually mediated as it was detectable during daylight and darkness.
  • Larva treated with the candidate compounds avoided the noxious stimuli analogously to vehicle control (Fig. 5R).
  • larval zebrafish swam spontaneously in an open arena and their locomotion exhibited a characteristic segmentation into an individual burst of locomotion, also called a swim bout.
  • the inventors traced larval swim locomotion in the presence of the candidate compounds and, subsequently, performed detailed kinematic analysis. Neither larval average swim speed, bout length, bout- nor interbout duration were altered by the candidate compounds (Fig. 5S).
  • all the candidate compounds selectively modulated feeding behavior in zebrafish larvae while they showed no detectable impact on development and did not interfere with the execution of an array of behavioral tasks.
  • oC compound A and B increased food intake with distinct temporal dynamics in ad libitum feed mice (Fig. 6B, C) but had no significant impact in 16 h fasted mice, probably due to an appetite ceiling effect (Fig. 6D).
  • Anamorelin had a similar impact on food intake as the oC compounds.
  • aC compound C and D reduced food intake in ad libitum fed and 16 h fasted mice with similar kinetics (Fig. 6B-D) based on a smaller meal size (Fig. 7C).
  • Rimonabant induced a more potent anorectic effect in the dark-phase compared to aC compounds, and also only rimonabant triggered compensatory food intake in the following light-phase (Fig. 7D).
  • the inventors tracked mice locomotion to quantify their spontaneous activity. None of the candidate compounds had an impact on undisturbed mice locomotion, whereas hypoglycemia induced by insulin injection reduced locomotion (Fig. 6E, F).
  • the inventors presented short light-flashes (5s) to which mice did not show a detectable locomotion response independent of treatment (Fig. 6G).
  • mice behavioral chamber causing mice to freeze
  • Fig. 6H Only rimonabant treatment modulated the response to the acoustic tap in mice as observed in zebrafish
  • Fig. 2K zebrafish
  • the inventors wanted to further benchmark the behavioral selectivity of our compounds by selecting additional behaviors based on the previously observed problems with appetite modulators: specifically, the inventors considered glucose homeostasis, psychiatric effects, and nausea.
  • blood glucose levels were not altered 30-min post candidate compound injection in mice, whereas insulin injection induced hypoglycemia (Fig. 6E). Blood glucose levels were similar across experimental groups’ prior to injection (Fig. 7E).
  • thigmotaxis in mice which is a behavioral index for anxiety. None of the candidate compounds modulated the thigmotaxis response, whereas rimonabant increased murine anxiety as reported previously (Fig. 6I).
  • the inventors demonstrated the existence of ideal, behavior-selective small molecules in two vertebrate species.
  • appetite modulators the inventors identified 268 compounds that are novel and to date have no described in vivo bioactivity. Twenty-two of these candidates were extensively validated and their behavioral selectivity confirmed in multiple follow-up studies. Furthermore, the majority of these did not bind to known receptors from main neurotransmitter systems.
  • the two orexigenic and two anorectic candidate compounds were benchmarked in a variety of sophisticated behavioral assays and were shown to exclusively modulate appetite in zebrafish and in mice.
  • the inventors performed a similar analysis for compounds selective for habituation (Fig. 7). In sum, the inventors identified ideal, behavior-selective small molecules, which exclusively promote or inhibit distinct vertebrate behaviors in two vertebrate species.
  • phenotype screens are their superior ability to identify“first-in-class” drugs compared to target-based strategies.
  • such screens only employ effect size in their hit selection criteria.
  • the inventors considered compound selectivity at the initial stage, which reduced the hit rate by ⁇ 50 % compared to the standard effect size criterion, and led to the selection of more specific in vivo phenotypes.
  • This selectivity can arise either from the interaction of compounds with unknown molecular targets that are unique to a behavior or from systemic drug action balanced optimally across different mechanisms. Both are impossible to identify without a whole-organism approach. Taking the above into account, future strategies should combine a series of complex behaviors - e.g.
  • the inventors unbiased and large-scale behavioral findings jointly establish the advantages of multi-behavioral screening for psychoactive compounds, propose a largely independent and modular organization of neural circuits that generate behavior in the larval zebrafish, and demonstrate the feasibility to control vertebrate behavior with novel, behavior- selective compounds.

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Abstract

La présente invention concerne des composés à petites molécules capables de moduler l'appétit chez un animal vertébré, en particulier chez un mammifère. L'invention concerne en outre l'utilisation des composés de l'invention dans des procédés de traitement de troubles de l'alimentation, et en tant qu'additif alimentaire pour la consommation humaine ou l'élevage d'animaux.
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