title: Discovery of the first thumb pocket 1 NS5B polymerase inhibitor (BILB 1941) with demonstrated antiviral activity in patients chronically infected with genotype 1 hepatitis C virus (HCV).
abstract: Combinations of direct acting antivirals (DAAs) that have the potential to suppress emergence of resistant virus and that can be used in interferon-sparing regimens represent a preferred option for the treatment of chronic HCV infection. We have discovered allosteric (thumb pocket 1) non-nucleoside inhibitors of HCV NS5B polymerase that inhibit replication in replicon systems. Herein, we report the late-stage optimization of indole-based inhibitors, which began with the identification of a metabolic liability common to many previously reported inhibitors in this series. By use of parallel synthesis techniques, a sparse matrix of inhibitors was generated that provided a collection of inhibitors satisfying potency criteria and displaying improved in vitro ADME profiles. "Cassette" screening for oral absorption in rat provided a short list of potential development candidates. Further evaluation led to the discovery of the first thumb pocket 1 NS5B inhibitor (BILB 1941) that demonstrated antiviral activity in patients chronically infected with genotype 1 HCV.
authors: Research and Development, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard Street, Laval, Quebec, H7S 2G5, Canada. pierre.beaulieu@boehringer-ingelheim.com
authors: Pierre L
authors: PL
authors: Beaulieu
authors: Michael
authors: M
authors: Bös
authors: Michael G
authors: MG
authors: Cordingley
authors: Catherine
authors: C
authors: Chabot
authors: Gulrez
authors: G
authors: Fazal
authors: Michel
authors: M
authors: Garneau
authors: James R
authors: JR
authors: Gillard
authors: Eric
authors: E
authors: Jolicoeur
authors: Steven
authors: S
authors: LaPlante
authors: Ginette
authors: G
authors: McKercher
authors: Martin
authors: M
authors: Poirier
authors: Marc-André
authors: MA
authors: Poupart
authors: Youla S
authors: YS
authors: Tsantrizos
authors: Jianmin
authors: J
authors: Duan
authors: George
authors: G
authors: Kukolj
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D008958:Models, Molecular; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase