Hepatitis C virus NS5A replication complex inhibitors. Part 6: Discovery of a novel and highly potent biarylimidazole chemotype with inhibitory activity toward genotypes 1a and 1b replicons.
A medicinal chemistry campaign that was conducted to address a potential genotoxic liability associated with an aniline-derived scaffold in a series of HCV NS5A inhibitors with dual GT-1a/-1b inhibitory activity is described. Anilides 3b and 3c were used as vehicles to explore structural modifications that retained antiviral potency while removing the potential for metabolism-based unmasking of the embedded aniline. This effort resulted in the discovery of a highly potent biarylimidazole chemotype that established a potency benchmark in replicon assays, particularly toward HCV GT-1a, a strain with significant clinical importance. Securing potent GT-1a activity in a chemotype class lacking overt structural liabilities was a critical milestone in the effort to realize the full clinical potential of targeting the HCV NS5A protein.
Departments of Discovery Chemistry, ‡Virology, §Lead Discovery and Optimization, ∥Computer-Assisted Drug Design, and ⊥Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Makonen
M
Belema
Van N
VN
Nguyen
Jeffrey L
JL
Romine
Denis R
DR
St Laurent
Omar D
OD
Lopez
Jason T
JT
Goodrich
Peter T
PT
Nower
Donald R
DR
O'Boyle
Julie A
JA
Lemm
Robert A
RA
Fridell
Min
M
Gao
Hua
H
Fang
Rudolph G
RG
Krause
Ying-Kai
YK
Wang
A Jayne
AJ
Oliver
Andrew C
AC
Good
Jay O
JO
Knipe
Nicholas A
NA
Meanwell
Lawrence B
LB
Snyder
D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D012093:Replicon / Q000187:drug effects*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase