title: Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir.
abstract: The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.
authors: Departments of Discovery Chemistry, ‡Discovery Chemistry Synthesis, §Computer-Assisted Drug Design, and ¶Pharmaceutical Candidate Optimization, #Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors: Makonen
authors: M
authors: Belema
authors: Van N
authors: VN
authors: Nguyen
authors: Carol
authors: C
authors: Bachand
authors: Dan H
authors: DH
authors: Deon
authors: Jason T
authors: JT
authors: Goodrich
authors: Clint A
authors: CA
authors: James
authors: Rico
authors: R
authors: Lavoie
authors: Omar D
authors: OD
authors: Lopez
authors: Alain
authors: A
authors: Martel
authors: Jeffrey L
authors: JL
authors: Romine
authors: Edward H
authors: EH
authors: Ruediger
authors: Lawrence B
authors: LB
authors: Snyder
authors: Denis R
authors: DR
authors: St Laurent
authors: Fukang
authors: F
authors: Yang
authors: Juliang
authors: J
authors: Zhu
authors: Henry S
authors: HS
authors: Wong
authors: David R
authors: DR
authors: Langley
authors: Stephen P
authors: SP
authors: Adams
authors: Glenn H
authors: GH
authors: Cantor
authors: Anjaneya
authors: A
authors: Chimalakonda
authors: Aberra
authors: A
authors: Fura
authors: Benjamin M
authors: BM
authors: Johnson
authors: Jay O
authors: JO
authors: Knipe
authors: Dawn D
authors: DD
authors: Parker
authors: Kenneth S
authors: KS
authors: Santone
authors: Robert A
authors: RA
authors: Fridell
authors: Julie A
authors: JA
authors: Lemm
authors: Donald R
authors: DR
authors: O'Boyle
authors: Richard J
authors: RJ
authors: Colonno
authors: Min
authors: M
authors: Gao
authors: Nicholas A
authors: NA
authors: Meanwell
authors: Lawrence G
authors: LG
authors: Hamann
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D002219:Carbamates; D004285:Dogs; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D011759:Pyrrolidines; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011759:Pyrrolidines; D014633:Valine; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir