title: Preclinical characterization of BMS-791325, an allosteric inhibitor of hepatitis C Virus NS5B polymerase.
abstract: BMS-791325 is an allosteric inhibitor that binds to thumb site 1 of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. BMS-791325 inhibits recombinant NS5B proteins from HCV genotypes 1, 3, 4, and 5 at 50% inhibitory concentrations (IC50) below 28 nM. In cell culture, BMS-791325 inhibited replication of HCV subgenomic replicons representing genotypes 1a and 1b at 50% effective concentrations (EC50s) of 3 nM and 6 nM, respectively, with similar (3 to 18 nM) values for genotypes 3a, 4a, and 5a. Potency against genotype 6a showed more variability (9 to 125 nM), and activity was weaker against genotype 2 (EC50, 87 to 925 nM). Specificity was demonstrated by the absence of activity (EC50s of >4 μM) against a panel of mammalian viruses, and cytotoxic concentrations (50%) were >3,000-fold above the HCV EC50. Resistance substitutions selected by BMS-791325 in genotype 1 replicons mostly mapped to a single site, NS5B amino acid 495 (P495A/S/L/T). Additive or synergistic activity was observed in combination studies using BMS-791325 with alfa interferon plus ribavirin, inhibitors of NS3 protease or NS5A, and other classes of NS5B inhibitor (palm site 2-binding or nucleoside analogs). Plasma and liver exposures in vivo in several animal species indicated that BMS-791325 has a hepatotropic disposition (liver-to-plasma ratios ranging from 1.6- to 60-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥ 10-fold above the inhibitor EC50s observed with HCV genotype 1 replicons. These findings support the evaluation of BMS-791325 in combination regimens for the treatment of HCV. Phase 3 studies are ongoing.
authors.affiliation: Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA julie.lemm@bms.com.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lemm
authors.affiliation: Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Mengping
authors.initials: M
authors.lastname: Liu
authors.affiliation: Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gentles
authors.affiliation: Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Ding
authors.affiliation: Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Voss
authors.affiliation: Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Lenore A
authors.initials: LA
authors.lastname: Pelosi
authors.affiliation: Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Ying-Kai
authors.initials: YK
authors.lastname: Wang
authors.affiliation: Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Rigat
authors.affiliation: Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Kathleen W
authors.initials: KW
authors.lastname: Mosure
authors.affiliation: Medicinal Chemistry, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Bender
authors.affiliation: Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Jay O
authors.initials: JO
authors.lastname: Knipe
authors.affiliation: Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Colonno
authors.affiliation: Medicinal Chemistry, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.affiliation: Medicinal Chemistry, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Kadow
authors.affiliation: Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Santone
authors.affiliation: Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Susan B
authors.initials: SB
authors.lastname: Roberts
authors.affiliation: Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Gao
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001552:Benzazepines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004285:Dogs; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D016898:Interferon-alpha / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D012093:Replicon / Q000187:drug effects; D012254:Ribavirin / Q000494:pharmacology; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*
chemical_list: C587012:8-cyclohexyl-N-((dimethylamino)sulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-((3-methyl-3,8-diazabicyclo(3.2.1)oct-8-yl)carbonyl)cycloprop(d)indolo(2,1-a)(2)benzazepine-5-carboxamide; D000998:Antiviral Agents; D001552:Benzazepines; D007211:Indoles; D016898:Interferon-alpha; D017361:Viral Nonstructural Proteins; D012254:Ribavirin; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
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