WO2000024725A1 - Composes pentacycliques utiles en tant qu'inhibiteurs de l'helicase de ns3 du virus de l'hepatite c - Google Patents

Composes pentacycliques utiles en tant qu'inhibiteurs de l'helicase de ns3 du virus de l'hepatite c Download PDF

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Publication number
WO2000024725A1
WO2000024725A1 PCT/US1999/025135 US9925135W WO0024725A1 WO 2000024725 A1 WO2000024725 A1 WO 2000024725A1 US 9925135 W US9925135 W US 9925135W WO 0024725 A1 WO0024725 A1 WO 0024725A1
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Prior art keywords
ring
optionally
compound
replaced
straight
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PCT/US1999/025135
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English (en)
Inventor
James W. Janetka
Brian E. Ledford
Michael D. Mullican
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Vertex Pharmaceuticals Incorporated
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Application filed by Vertex Pharmaceuticals Incorporated filed Critical Vertex Pharmaceuticals Incorporated
Priority to AU13243/00A priority Critical patent/AU1324300A/en
Publication of WO2000024725A1 publication Critical patent/WO2000024725A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a non-condensed 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
    • C07D417/02—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 two hetero rings
    • C07D417/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to compounds which are useful in inhibiting the hepatitis C virus NS3 helicase. These compounds are useful in pharmaceutical compositions and method for treating and preventing HCV infection.
  • HCV hepatitis C virus
  • the HCV genome encodes a polyprotein of 3010- 3033 amino acids [Choo, Q.-L., et al . "Genetic
  • the HCV nonstructural (NS) proteins are presumed to provide the essential catalytic machinery for viral replication.
  • the NS proteins are derived by proteolytic cleavage of the polyprotein [Bartentscher, R. et al., "Nonstructural Protein 3 of the Hepatitis C Virus Encodes a Serine-Type Proteinase Required for Cleavage at the NS3/4 and NS4/5 Junctions", J. Virol., 67, pp. 3835-3844 (1993); Grakoui, A. et al. "Characterization of the Hepatitis C Virus-Encoded Serine Proteinase: Determination of Proteinase-Dependent Polyprotein Cleavage Sites", J.
  • NS2 encodes a presumed etalloprotease
  • NS5B is a RNA-dependent RNA polymerase
  • NS3 is a bifunctional enzyme with a serine protease localized to the N-terminal 181 residues of the protein and a RNA helicase in the C- terminal 465 amino acids.
  • the NS3 protease performs an intramolecular cleavage at the NS3/NS4A junction to form a tight noncovalent NS3-NS4A complex necessary for efficient processing of the remaining polyprotein [C. Failla et al., J. Virol., 69, pp. 1769-1777 (1995); R. Bartenschlager et al., J. Virol., 69, pp. 7519-7528 (1995); Y. Tanji et al . , J. Virol., 69, pp. 1575-1581 (1995)].
  • the serine protease and helicase domains are separated by proteolytic processing of NS3 in vivo. This may reflect economical packaging of these enzymatic components, or could imply a functional interdependence between the two domains.
  • NS3 can be expressed independently and isolated as catalytically active species.
  • NS3 can be expressed independently and isolated as catalytically active species.
  • NS3 protease and helicase domains may contact one another and modulate NS3 catalytic activities. Examples include apparent differences in pH optima of ATPase and RNA unwinding activities between a contiguous NS3 protein complexed
  • the present invention provides compounds which inhibit HCV NS3 helicase. These compounds are mono-, di- and tri-substituted pentacycles, wherein the pentacyclic ring may contain up to 3 heteroatoms and may be saturated, partially unsaturated or fully unsaturated.
  • compositions useful for the treatment and the prevention of HCV infection may be formulated into pharmaceutically acceptable compositions useful for the treatment and the prevention of HCV infection.
  • Such compositions and the methods of using them to treat or prevent HCV infection are also part of the present invention.
  • the present invention provides a compound by formula 1:
  • each ring comprises 5 to 6 ring atoms independently selected from C, N, 0 or S; ii. no more than 4 ring atoms are selected from N, 0 or S; iii. any CH 2 is optionally replaced with C(0); iv. any S is optionally replaced with S (0) or S(0 2 ); v. up to 3 hydrogen atom bound to said ring atoms are optionally and independently replaced with R', R 2 , or R 3 ; and vi .
  • each of X 1 , X 2 , and X 3 are independently selected from C, CH, CH 2 , N, NH, 0, S, S (0) or S (0 2 ) , wherein any hydrogen atom present in X 2 or X 3 is optionally and independently replaced with R 1 , R 2 , or R 3 ;
  • Y is selected from -OH, -N(R 4 ) 2 ,-SH , -S(0 2 )R 4 ,
  • each R 1 is independently selected from H, (Ci- Ce) -straight or branched alkyl, or (C 2 -C 6 ) -straight or branched alkenyl, wherein up to 2 hydrogen atoms in said alkyl or alkenyl are optionally and independently replaced with R 2 or R 3 ; each R 2 is a monocyclic or
  • each ring comprises 5 to 6 ring atoms independently selected from C, N, 0 or S; ii. no more than 4 ring atoms are selected from N, 0 or S; iii. any CH 2 is optionally replaced with C(O); iv. any S is optionally replaced with S(O) or S(0) 2 ; and v.
  • up to 3 hydrogen atoms bound to said ring atoms are optionally and independently replaced with R 3 or (CH 2 ) n R 3 ; wherein n is 1, 2 or 3; each R J is independently selected from -F, -Cl, -Br, -I, -CN, -N0 2 , -CF 3 , -OCF 3 , -OR 4 , -OC(0)R 4 , -OC(0)OR 4 ,
  • each R 4 is independently selected from H, (C ⁇ -C 6 ) - straight or branched
  • each ring comprises 5 to 6 ring atoms independently selected from C, N, 0 or S; ii. no more than 4 ring atoms are selected from N, 0 or S; iii. any CH 2 is optionally replaced with C(O); iv. any S is optionally replaced with S (0) or S (0) 2 ; and v. up to 3 hydrogen atoms bound to said ring atoms are optionally and independently replaced with Ci-C ⁇ straight or branched alkyl.
  • alkyl when used to define L 1 or L 2 denote straight or branched chains which are bound to the rest of the molecules at two ends (i.e., one end is bound to W ⁇ (or W 2 ) and the other is bound to X 1 (or C) ) .
  • alkyl alkenyl and alkynyl
  • L 1 or L 2 denote straight or branched chains which are bound to the rest of the molecules at two ends (i.e., one end is bound to W ⁇ (or W 2 ) and the other is bound to X 1 (or C) ) .
  • alkyl alkenyl
  • alkynyl when used to define L 1 or L 2 denote straight or branched chains which are bound to the rest of the molecules at two ends (i.e., one end is bound to W ⁇ (or W 2 ) and the other is bound to X 1 (or C) ) .
  • alkyl alkenyl
  • alkynyl have a slightly different meaning than that
  • L 1 is a C 3 straight alkyl chain
  • the portion of the molecule containing L 1 would be represented by W 1 -CH 2 -CH 2 -CH 2 -X 1 .
  • L 1 is -CH 2 -CH 2 -CH 2 -, rather than the accepted definition of a C3 straight alkyl chain —
  • the above definitions include certain polymers and multimers which are not part of the present invention.
  • R 3 replaces a hydrogen atom in W 1 , 2 , R x or R 2
  • any R 4 present in said hydrogen atom- replacing R 3 group is not substituted with R 2 .
  • This restriction eliminates those undesired polymers.
  • the invention includes all stereoisomers and racemic forms of the above compounds.
  • the invention also includes pharmaceutically acceptable salts of the compounds.
  • the invention includes tautomers of the above compounds .
  • the term "monocyclic ring system", as used herein, includes saturated, partially unsaturated and • fully unsaturated ring structures.
  • bicyclic ring system includes systems wherein each ring is independently saturated, partially unsaturated and fully unsaturated.
  • monocyclic and bicyclic ring systems useful in W 1 , W 2 and R 2 include, but are not limited to, cyclopentane, cyclopentene, indane, indene, cyclohexane, cyclohexene, cyclohexadiene, benzene, tetrahydronaphthalene, decahydronaphthalene, naphthalene, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, 1, 2, 3-triazine, 1,2,4 - triazine, 1, 3, 5-triazine, 1, 2, 3, 4-tetrazine, 1,2,4,5- tetrazine, 1, 2, 3, 4-tetrahydroquinoIine, quinoline, 1, 2, 3, 4-tetrahydroisoquinoline, isoquinoline
  • heterocycles referred may be attached to the rest of the compound by any atom of the heterocycle which results m the creation of a stable structure.
  • ring atom refers to a backbone atom that makes up the ring. Such ring atoms are selected from C, N, 0 or S and are bound to 2 or 3 other such ring atoms (3 in the case of certain ring atoms in a bicyclic ring system) .
  • ring atom does not include hydrogen.
  • X 1 is N
  • X 2 is S
  • X 3 is N
  • X 2 and X J has the structure:
  • one of L 1 or L 2 is a single bond and the other is a single bond or methylene.
  • Y is -OH or N(R) 2 . Even more preferred is when Y is -NH(R 4 ) . Most preferred is when Y is NH 2 .
  • neither W 1 nor W is hydrogen.
  • at least one of W or W 2 is phenyl, methylphenyl or chlorophenyl and the other is selected from phenyl, methylphenyl, chlorophenyl, ethylphenyl, isopropylphenyl, t-butylphenyl, methoxyphenyl, cyclohexylphenyl, bisphenyl, furyl, thiophenyl, benzothiophenyl, naphthyl, phenylmethylphenyl, 3-chloro-4-methylphenyl, 3-fluoro-4- methylphenyl, methoxycarboxyphenyl, fluorenyl, oxofluorenyl, oxobenzochromenyl, phenoxyphenyl, benzyloxyphenyl, indanyl, benzoylphenyl, 3,4- methylenedioxyphenyl, hydroxy
  • the HCV NS3 helicase contains a binding site for ATP (which is cleaved by the ATPase activity of the helicase) and a separate binding site for double-stranded polynucleotides (which are unwound by the unwinding activity of the helicase) .
  • the energy generated by cleavage of ATP is required for the unwinding activity.
  • the compounds of this invention are designed to bind Hepatitis C helicase and therefore are expected to inhibit, either directly or indirectly, the unwinding activity of the helicase. Therefore, the compounds of this invention can be assayed for their ability to inhibit ATP cleavage or to inhibit unwinding activity. Assays for each of the activities are known in the art [M. E. Pullman et al . , "Partial Resolution of the Enzymes Catalyzing Oxidative Phosphorylation", J. Biol. Chem., 235, pp. 3322-28 (1980); C. H. Gross et al .
  • the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable salt thereof, as described above, and a pharmaceutically acceptable carrier. If pharmaceutically acceptable salts of the compounds of this invention are utilized in these compositions, those salts are preferably derived from inorganic or organic acids and bases.
  • acid salts include the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobro ide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl- propionate, picrate, pivalate, propionate, succinate, tartrate, thi
  • Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D- glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such
  • compositions and methods of this invention may also be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial g
  • compositions of this invention are formulated for pharmaceutical administration to a mammal, preferably a human being.
  • Such pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra- synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1, 3-butanediol .
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides .
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oils such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as those described in Pharmacopeia Helvetica (Ph. Helv. ) or similar alcohol.
  • the pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non- irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non- irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • the pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • the amount of compound present in the above- described composition should be sufficient to cause a detectable decrease in ATPase activity and/or unwinding activity of the HCV NS3 helicase, as measured by any of the assays described in the examples.
  • compositions of this invention may further comprise an anti-viral agent effective against hepatitis C virus infection.
  • agents include, but are not limited to, inhibitors of HCV N ⁇ 3 protease, such as those described in WO 98/17679; inhibitors of HCV polymerase; IMPDH inhibitors, such as mycophenolic acid, mycophenolate mofetil, and those described in any of United States Patents 5,380,879; 5,441,953; 5,493,030; 5,633,279;
  • the amount of the anti-viral agent present in the compositions of this invention should be between 10- 100% of the amount of that agent normally used in a monotherapy for anti-viral activity. Such amounts are known in the art and/or described in the patent applications referred to above.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of active ingredients will also depend upon the particular compound and anti-viral agent, if present, in the composition.
  • the invention provides a method of detecting HCV helicase activity in a biological sample suspected of containing a polypeptide having HCV NS3 helicase activity comprising the step of contacting said biological sample with a compound of this invention.
  • biological sample includes cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • biological sample also includes living organisms, in which case "contacting a compound of this invention with a biological sample suspected of containing HCV NS3 helicase” is synonymous with the term “administrating said compound to the living organism.
  • polypeptide having HCV helicase activity means any polypeptide which demonstrates activity in at least, but not limited to, the unwinding assay described in Example 57.
  • that term means a polypeptide encoded by a naturally occurring or an experimentally produced strain of hepatitis C virus or a polypeptide having a consensus amino acid sequence derived from polypeptides having the aforementioned activities encoded by two or more strains of hepatitis C virus.
  • detecting HCV helicase activity includes inhibiting the helicase activity, if present, in said sample; determining the presence or absence of HCV helicase activity in said sample; quantitating the HCV helicase activity in said sample; and, in the case of a living organism, treating and/or reducing the severity of an HCV viral infection.
  • the invention provides a method of treating an HCV viral infection in a mammal comprising the step of administering to said mammal a pharmaceutically acceptable composition described above.
  • the patient if the patient is also administered an anti-viral agent, it may be delivered together with the compound of this invention in a single dosage form, or, as a separate dosage form.
  • the antiviral agent may be administered prior to, at the same time as, or following administration of a pharmaceutically acceptable composition comprising a compound of this invention.
  • the crude i ino chloride (prepared from 2.0 of benzanilide by similar method described in Example 1, Step 3) was dissolved in 10 mL of acetone and treated with 2.0 g (24.7 mmol) of sodium thiocyanate. The resulting orange suspension was stirred at room temperature for 8 hrs and filtered. The filtrate, containing the crude isothiocyanate, was concentrated to an orange crystalline solid and dissolved in 10 mL of acetonitrile. The reaction mixture was then treated with 3.0 mL (38.7 mmol) of 40% solution of aqueous methylamine. The resulting yellow solution was allowed to stir at room temperature for 8 hrs and then decanted to remove a small amount of black precipitate.
  • RNA/DNA hybrid The standard 3 '-tailed double-stranded RNA/DNA hybrid was prepared as described as follows.
  • the long 98-nucleotide (“nt") RNA template was transcribed from a BsrBI-digested plasmid pSP65 (Promega, Madison, WI) in the presence of [ ⁇ - 3 2p-GTP] (New England Nuclear, Boston, MA) .
  • the short 34-nt DNA release strand corresponds to a SP6 RNA transcript from a BamHI-digested pSP64 (Promega) .
  • Standard helicase reactions (20 ⁇ l) were carried out as follows.
  • HCV NS3 helicase (0.3 or 1 nM) was added to a mixture of 25 mM morpholinepropanesulfonic acid (MOPS)-NaOH (pH 6.5), 1 mM ATP, 0.5 mM MnCl2, 2 mM dithiothreitol (DTT), 0.1 mg of bovine serum albumin
  • ATPase activity of HCV NS3 helicase in the presence or absence of inhibitor was monitored by following the rate of ADP production using a coupled enzyme assay. In this assay, an amount of NADH equal to ADP is oxidized to NAD + resulting in a decrease in absorbance at 340 nm.
  • a reaction mix consisting of buffer, pH 7.0, coupling enzyme components, poly(rU), and HCV NS3 helicase was prepared and aliquoted into wells. Various concentrations of inhibitor in DMSO were added to the wells and incubated for 15 minutes at 30°C. Reactions were initiated with ATP.
  • the final concentrations of assay components in 200 ⁇ l reaction are as follows: 44 mM MOPS, pH 7.0, 8.8 mM NaCl, 2.2 mM MgCl 2 , 17.6% v/v glycerol, 2.5 mM PEP, 0.2 mM NADH, 12.5 ⁇ g/mL pyruvate kinase, 12.5 ⁇ g/mL lactate dehydrogenase, 1 ⁇ M poly(rU), 2 nM HCV NS3 helicase, 2% DMSO with varying concentrations of inhibitor, and 100 ⁇ M ATP.
  • B, and X are the observed rate, inverse of maximum rate in the absence of inhibitor, and inhibitor concentration, respectively.
  • ATPase activity of HCV helicase in the presence or absence of inhibitor was also measured by quantifying the ADP produced from ATP using an HPLC method.
  • a reaction mix consisting of buffer, pH 7.0, poly(rU), and HCV NS3 helicase was prepared and aliquoted into wells. Various concentrations of inhibitor in DMSO were added to the wells and incubated for 15 minutes at 30°C. Reactions were initiated with ATP.
  • the final concentrations of assay components in 200 ⁇ l reaction are as follows: 44 mM MOPS, pH 7.0, 8.8 mM NaCl, 2.2 mM MgCl 2 , 17.6% v/v glycerol, 1 ⁇ M poly(rU), 2 nM trHCV NS3 Helicase, 2% DMSO with varying concentrations of inhibitor, and 100 ⁇ M ATP.

Abstract

L'invention concerne des composés servant à inhiber l'hélicase de NS3 du virus de hépatite C. Ces composés sont utiles dans des compositions pharmaceutiques et dans des méthodes de traitement et de prévention de la contamination par VHC.
PCT/US1999/025135 1998-10-26 1999-10-26 Composes pentacycliques utiles en tant qu'inhibiteurs de l'helicase de ns3 du virus de l'hepatite c WO2000024725A1 (fr)

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AU13243/00A AU1324300A (en) 1998-10-26 1999-10-26 Pentacyclic compounds useful as inhibitors of hepatitis c virus ns3 helicase

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US10564898P 1998-10-26 1998-10-26
US60/105,648 1998-10-26

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EP1881828A1 (fr) * 2005-05-20 2008-01-30 Valeant Research & Development Traitement de l'hepatite c (hcv) au moyen de doses sous-therapeutiques de ribavirine
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US8247453B2 (en) 2008-02-21 2012-08-21 Janssen Pharmaceutica, Nv Methods for the treatment of dermatological disorders
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EP2888010A4 (fr) * 2012-08-22 2016-07-20 Univ Cornell Méthodes d'inhibition de la fascine
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