title: Discovery of hepatitis C virus NS3-4A protease inhibitors with improved barrier to resistance and favorable liver distribution.
abstract: Given the emergence of resistance observed for the current clinical-stage hepatitis C virus (HCV) NS3 protease inhibitors, there is a need for new inhibitors with a higher barrier to resistance. We recently reported our rational approach to the discovery of macrocyclic acylsulfonamides as HCV protease inhibitors addressing potency against clinically relevant resistant variants. Using X-ray crystallography of HCV protease variant/inhibitor complexes, we shed light on the complex structural mechanisms by which the D168V and R155K residue mutations confer resistance to NS3 protease inhibitors. Here, we disclose SAR investigation and ADME/PK optimization leading to the identification of inhibitors with significantly improved potency against the key resistant variants and with increased liver partitioning.
authors.affiliation: Department of Medicinal Chemistry and ‡Department of Biological Sciences, Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
authors.forename: Benoît
authors.initials: B
authors.lastname: Moreau
authors.forename: Jeff A
authors.initials: JA
authors.lastname: O'Meara
authors.forename: Josée
authors.initials: J
authors.lastname: Bordeleau
authors.forename: Michel
authors.initials: M
authors.lastname: Garneau
authors.forename: Cedrickx
authors.initials: C
authors.lastname: Godbout
authors.forename: Vida
authors.initials: V
authors.lastname: Gorys
authors.forename: Mélissa
authors.initials: M
authors.lastname: Leblanc
authors.forename: Elisia
authors.initials: E
authors.lastname: Villemure
authors.forename: Peter W
authors.initials: PW
authors.lastname: White
authors.forename: Montse
authors.initials: M
authors.lastname: Llinàs-Brunet
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D011480:Protease Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C080106:NS4A protein, flavivirus