title: Discovery of ABT-267, a pan-genotypic inhibitor of HCV NS5A.
abstract: We describe here N-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds with 2S,5S stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to the 2R,5R analogues. Furthermore, the attachment of substituents at the 4-position of the central N-phenyl group resulted in compounds with improved potency. Substitution with tert-butyl, as in compound 38 (ABT-267), provided compounds with low-picomolar EC50 values and superior pharmacokinetics. It was discovered that compound 38 was a pan-genotypic HCV inhibitor, with an EC50 range of 1.7-19.3 pM against GT1a, -1b, -2a, -2b, -3a, -4a, and -5a and 366 pM against GT6a. Compound 38 decreased HCV RNA up to 3.10 log10 IU/mL during 3-day monotherapy in treatment-naive HCV GT1-infected subjects and is currently in phase 3 clinical trials in combination with an NS3 protease inhibitor with ritonavir (r) (ABT-450/r) and an NS5B non-nucleoside polymerase inhibitor (ABT-333), with and without ribavirin.
authors.affiliation: Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: DeGoey
authors.forename: John T
authors.initials: JT
authors.lastname: Randolph
authors.forename: Dachun
authors.initials: D
authors.lastname: Liu
authors.forename: John
authors.initials: J
authors.lastname: Pratt
authors.forename: Charles
authors.initials: C
authors.lastname: Hutchins
authors.forename: Pamela
authors.initials: P
authors.lastname: Donner
authors.forename: A Chris
authors.initials: AC
authors.lastname: Krueger
authors.forename: Mark
authors.initials: M
authors.lastname: Matulenko
authors.forename: Sachin
authors.initials: S
authors.lastname: Patel
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Motter
authors.forename: Lissa
authors.initials: L
authors.lastname: Nelson
authors.forename: Ryan
authors.initials: R
authors.lastname: Keddy
authors.forename: Michael
authors.initials: M
authors.lastname: Tufano
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Caspi
authors.forename: Preethi
authors.initials: P
authors.lastname: Krishnan
authors.forename: Neeta
authors.initials: N
authors.lastname: Mistry
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Koev
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Reisch
authors.forename: Rubina
authors.initials: R
authors.lastname: Mondal
authors.forename: Tami
authors.initials: T
authors.lastname: Pilot-Matias
authors.forename: Yi
authors.initials: Y
authors.lastname: Gao
authors.forename: David W A
authors.initials: DW
authors.lastname: Beno
authors.forename: Clarence J
authors.initials: CJ
authors.lastname: Maring
authors.forename: Akhter
authors.initials: A
authors.lastname: Molla
authors.forename: Emily
authors.initials: E
authors.lastname: Dumas
authors.forename: Andrew
authors.initials: A
authors.lastname: Campbell
authors.forename: Laura
authors.initials: L
authors.lastname: Williams
authors.forename: Christine
authors.initials: C
authors.lastname: Collins
authors.forename: Rolf
authors.initials: R
authors.lastname: Wagner
authors.forename: Warren M
authors.initials: WM
authors.lastname: Kati
mesh_terms: D015081:2-Naphthylamine; D000813:Anilides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002219:Carbamates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D055808:Drug Discovery; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D011392:Proline; D051381:Rats; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014633:Valine; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D015081:2-Naphthylamine; D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D011392:Proline; D013449:Sulfonamides; D014498:Uracil; D014633:Valine; D017361:Viral Nonstructural Proteins; C586094:ombitasvir; C588260:dasabuvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase