Inhibitors of hepatitis C virus polymerase: synthesis and characterization of novel 2-oxy-6-fluoro-N-((S)-1-hydroxy-3-phenylpropan-2-yl)-benzamides.
SAR exploration from an initial hit, (S)-N-(2-cyclohexenylethyl)-2-fluoro-6-(2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoethoxy)benzamide (1), identified using our proprietary automated ligand identification system (ALIS),(1) has led to a novel series of selective hepatitis C virus (HCV) NS5B polymerase inhibitors with improved in vitro potency as exemplified by (S)-2-fluoro-6-(2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoethoxy)-N-isopentyl-N-methylbenzamidecarboxamide (41) (IC(50)=0.5 microM). The crystal structure of an analogue (44) was solved and provided rationalization of the SAR of this series, which binds in a distinct manner in the palm domain of NS5B, consistent with biochemical analysis using enzyme mutant variants. These data warrant further lead optimization efforts on this novel series of non-nucleoside inhibitors targeting the HCV polymerase.
Cheng
Cliff C
CC
Department of Lead Discovery, Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, United States. cccheng@alum.mit.edu
Shipps
Gerald W
GW
Yang
Zhiwei
Z
Kawahata
Noriyuki
N
Lesburg
Charles A
CA
Duca
José S
JS
Bandouveres
Jamie
J
Bracken
Jack D
JD
Jiang
Chuan-kui
CK
Agrawal
Sony
S
Ferrari
Eric
E
Huang
H-C
HC
D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D003461:Crystallography; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D016174:Hepacivirus / Q000201:enzymology*; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D008958:Models, Molecular; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D000998:Antiviral Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase