Inhibitors of HCV NS5B polymerase. Part 1: Evaluation of the southern region of (2Z)-2-(benzoylamino)-3-(5-phenyl-2-furyl)acrylic acid.
A novel series of nonnucleoside HCV NS5B polymerase inhibitors were prepared from (2Z)-2-(benzoylamino)-3-(5-phenyl-2-furyl)acrylic acid, a high throughput screening lead. SAR studies combined with structure based drug design focusing on the southern heterobiaryl region of the template led to the synthesis of several potent and orally bioavailable lead compounds. X-ray crystallography studies were also performed to understand the interaction of these inhibitors with HCV NS5B polymerase.
Pfefferkorn
Jeffrey A
JA
Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. jeffrey.a.pfefferkorn@pfizer.com
Greene
Meredith L
ML
Nugent
Richard A
RA
Gross
Rebecca J
RJ
Mitchell
Mark A
MA
Finzel
Barry C
BC
Harris
Melissa S
MS
Wells
Peter A
PA
Shelly
John A
JA
Anstadt
Robert A
RA
Kilkuskie
Robert E
RE
Kopta
Laurice A
LA
Schwende
Francis J
FJ
D000179:Acrylates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005663:Furans / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
D000179:Acrylates; D004791:Enzyme Inhibitors; D005663:Furans; D017361:Viral Nonstructural Proteins; C504279:(2Z)-2-(benzoylamino)-3-(5-phenyl-2-furyl)acrylic acid; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C036658:acrylic acid