title: The discovery of potent nonstructural protein 5A (NS5A) inhibitors with a unique resistance profile-Part 1.
abstract: Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol-Myers-Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl-imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)-1-((S)-2-(4-(4-(6-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)quinoxalin-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (17), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half-life. This compound represents a promising lead that warrants further evaluation.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research & Development, Ramsgate Road, Sandwich, Kent CT13 9NJ (UK).
authors.forename: Thien Duc
authors.initials: TD
authors.lastname: Tran
authors.forename: Florian
authors.initials: F
authors.lastname: Wakenhut
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: Rebecca A
authors.initials: RA
authors.lastname: Brimage
authors.forename: Rebecca
authors.initials: R
authors.lastname: Halstead
authors.forename: Rebecca
authors.initials: R
authors.lastname: Glen
authors.forename: Craig P
authors.initials: CP
authors.lastname: Wilson
authors.forename: Fiona
authors.initials: F
authors.lastname: Adam
authors.forename: Duncan
authors.initials: D
authors.lastname: Hay
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: 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 / Q000493:pharmacokinetics; D002460:Cell Line; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D006207:Half-Life; D016174:Hepacivirus / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D014633:Valine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D011810:Quinoxalines; D014633:Valine; D017361:Viral Nonstructural Proteins; C000601186:methyl (1-(2-(4-(4-(6-(2-(1-((methoxycarbonyl)valyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)quinoxalin-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: HCV; NS5A; antiviral agents; drug resistance; hepatitis C virus; viral proteases