title: Discovery of novel highly potent hepatitis C virus NS5A inhibitor (AV4025).
abstract: A series of next in class small-molecule hepatitis C virus (HCV) NS5A inhibitors with picomolar potency containing 2-pyrrolidin-2-yl-5-{4-[4-(2-pyrrolidin-2-yl-1H-imidazol-5-yl)buta-1,3-diynyl]phenyl}-1H-imidazole cores was designed based on the SAR studies available for the reported NS5A inhibitors. Compound 13a (AV4025), with (S,S,S,S)-stereochemistry (EC50 = 3.4 ± 0.2 pM, HCV replicon genotype 1b), was dramatically more active than were the compounds with two (S)- and two (R)-chiral centers. Human serum did not significantly reduce the antiviral activity (<4-fold). Relatively favorable pharmacokinetic features and good oral bioavailability were observed during animal studies. Compound 13a was well tolerated in rodents (in mice, LD50 = 2326 mg/kg or higher), providing a relatively high therapeutic index. During safety, pharmacology and subchronic toxicity studies in rats and dogs, it was not associated with any significant pathological or clinical findings. This compound is currently being evaluated in phase I/II clinical trials for the treatment of HCV infection.
authors.affiliation: Alla Chem LLC , 1835 East Hallandale Beach Boulevard 442, Hallandale Beach, Florida 33009, United States.
authors.forename: Alexandre V
authors.initials: AV
authors.lastname: Ivachtchenko
authors.forename: Oleg D
authors.initials: OD
authors.lastname: Mitkin
authors.forename: Pavel M
authors.initials: PM
authors.lastname: Yamanushkin
authors.forename: Irina V
authors.initials: IV
authors.lastname: Kuznetsova
authors.forename: Elena A
authors.initials: EA
authors.lastname: Bulanova
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Shevkun
authors.forename: Angela G
authors.initials: AG
authors.lastname: Koryakova
authors.forename: Ruben N
authors.initials: RN
authors.lastname: Karapetian
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Bichko
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Trifelenkov
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Kravchenko
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Vostokova
authors.forename: Mark S
authors.initials: MS
authors.lastname: Veselov
authors.forename: Nina V
authors.initials: NV
authors.lastname: Chufarova
authors.forename: Yan A
authors.initials: YA
authors.lastname: Ivanenkov
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D002522:Chlorocebus aethiops; D002986:Clinical Trials as Topic; D004285:Dogs; D055808:Drug Discovery; D005260:Female; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D051381:Rats; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D007093:Imidazoles; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase