title: Preclinical Profile and Characterization of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir (BMS-650032).
abstract: Asunaprevir (ASV; BMS-650032) is a hepatitis C virus (HCV) NS3 protease inhibitor that has demonstrated efficacy in patients chronically infected with HCV genotype 1 when combined with alfa interferon and/or the NS5A replication complex inhibitor daclatasvir. ASV competitively binds to the NS3/4A protease complex, with K(i) values of 0.4 and 0.24 nM against recombinant enzymes representing genotypes 1a (H77) and 1b (J4L6S), respectively. Selectivity was demonstrated by the absence of any significant activity against the closely related GB virus-B NS3 protease and a panel of human serine or cysteine proteases. In cell culture, ASV inhibited replication of HCV replicons representing genotypes 1 and 4, with 50% effective concentrations (EC(50)s) ranging from 1 to 4 nM, and had weaker activity against genotypes 2 and 3 (EC(50), 67 to 1,162 nM). Selectivity was again demonstrated by the absence of activity (EC(50), >12 μM) against a panel of other RNA viruses. ASV exhibited additive or synergistic activity in combination studies with alfa interferon, ribavirin, and/or inhibitors specifically targeting NS5A or NS5B. Plasma and tissue exposures in vivo in several animal species indicated that ASV displayed a hepatotropic disposition (liver-to-plasma ratios ranging from 40- to 359-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥110-fold above the inhibitor EC(50)s observed with HCV genotype-1 replicons. Based on these virologic and exposure properties, ASV holds promise for future utility in a combination with other anti-HCV agents in the treatment of HCV-infected patients.
authors.affiliation: Discovery Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA. fiona.mcphee@bms.com
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
authors.forename: Amy K
authors.initials: AK
authors.lastname: Sheaffer
authors.forename: Jacques
authors.initials: J
authors.lastname: Friborg
authors.forename: Dennis
authors.initials: D
authors.lastname: Hernandez
authors.forename: Paul
authors.initials: P
authors.lastname: Falk
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Zhai
authors.forename: Steven
authors.initials: S
authors.lastname: Levine
authors.forename: Susan
authors.initials: S
authors.lastname: Chaniewski
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.forename: Diana
authors.initials: D
authors.lastname: Barry
authors.forename: Chaoqun
authors.initials: C
authors.lastname: Chen
authors.forename: Min S
authors.initials: MS
authors.lastname: Lee
authors.forename: Kathy
authors.initials: K
authors.lastname: Mosure
authors.forename: Li-Qiang
authors.initials: LQ
authors.lastname: Sun
authors.forename: Michael
authors.initials: M
authors.lastname: Sinz
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Colonno
authors.forename: Jay
authors.initials: J
authors.lastname: Knipe
authors.forename: Paul
authors.initials: P
authors.lastname: Scola
mesh_terms: D000818:Animals; D002460:Cell Line; D004285:Dogs; D005838:Genotype; D000882:Haplorhini; D016174:Hepacivirus / Q000187:drug effects* / Q000472:pathogenicity*; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D007546:Isoquinolines; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C571889:asunaprevir