title: The discovery of potent nonstructural protein 5A (NS5A) inhibitors with a unique resistance profile-Part 2.
abstract: In ongoing studies towards novel hepatitis C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl-linked pyrrolidine NS5A replication complex inhibitors were probed and structure-activity relationships were elucidated. Using molecular modelling and a supercritical fluid chromatographic (SFC) technique, intramolecular H-bonding and peripheral functional group topology were evaluated as key determinants of activity and membrane permeability. The novel compounds exhibited retained potency as compared with the lead compounds, and also showed promising results against a panel of resistance viruses. Together, the results of the study take us a step closer towards understanding the potency of daclatasvir, a clinical candidate upon which the compounds were based, and to designing improved analogues as second-generation antiviral agents targeting NS5A.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research & Development, Ramsgate Road, Sandwich, Kent CT13 9NJ (UK).
authors.forename: Florian
authors.initials: F
authors.lastname: Wakenhut
authors.forename: Thien Duc
authors.initials: TD
authors.lastname: Tran
authors.forename: Chris
authors.initials: C
authors.lastname: Pickford
authors.forename: Stephen
authors.initials: S
authors.lastname: Shaw
authors.forename: Mike
authors.initials: M
authors.lastname: Westby
authors.forename: Caroline
authors.initials: C
authors.lastname: Smith-Burchnell
authors.forename: Lesa
authors.initials: L
authors.lastname: Watson
authors.forename: Michael
authors.initials: M
authors.lastname: Paradowski
authors.forename: Jared
authors.initials: J
authors.lastname: Milbank
authors.forename: David
authors.initials: D
authors.lastname: Stonehouse
authors.forename: Kathy
authors.initials: K
authors.lastname: Cheung
authors.forename: Robert
authors.initials: R
authors.lastname: Wybrow
authors.forename: Felice
authors.initials: F
authors.lastname: Daverio
authors.forename: Samuel
authors.initials: S
authors.lastname: Crook
authors.forename: Keith
authors.initials: K
authors.lastname: Statham
authors.forename: David
authors.initials: D
authors.lastname: Leese
authors.forename: Darren
authors.initials: D
authors.lastname: Stead
authors.forename: Fiona
authors.initials: F
authors.lastname: Adam
authors.forename: Duncan
authors.initials: D
authors.lastname: Hay
authors.forename: Lee R
authors.initials: LR
authors.lastname: Roberts
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Chiva
authors.forename: Carly
authors.initials: C
authors.lastname: Nichols
authors.forename: David C
authors.initials: DC
authors.lastname: Blakemore
authors.forename: Gilles H
authors.initials: GH
authors.lastname: Goetz
authors.forename: Ye
authors.initials: Y
authors.lastname: Che
authors.forename: Iain
authors.initials: I
authors.lastname: Gardner
authors.forename: Satish
authors.initials: S
authors.lastname: Dayal
authors.forename: Andrew
authors.initials: A
authors.lastname: Pike
authors.forename: Rob
authors.initials: R
authors.lastname: Webster
authors.forename: David C
authors.initials: DC
authors.lastname: Pryde
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: HCV; NS5A; antiviral agents; drug resistance; hepatitis C virus; viral RNA replication