Discovery of a novel class of potent HCV NS4B inhibitors: SAR studies on piperazinone derivatives.
HTS screening identified compound 2a (piperazinone derivative) as a low micromolar HCV genotype 1 (GT-1) inhibitor. Resistance mapping studies suggested that this piperazinone chemotype targets the HCV nonstructural protein NS4B. Extensive SAR studies were performed around 2a and the amide function and the C-3/C-6 cis stereochemistry of the piperazinone core were essential for HCV activity. A 10-fold increase in GT-1 potency was observed when the chiral phenylcyclopropyl amide side chain of 2a was replaced with p-fluorophenylisoxazole-carbonyl moiety (67). Replacing the C-6 nonpolar hydrophobic moiety of 67 with a phenyl moiety (95) did not diminish the GT-1 potency. A heterocyclic thiophene moiety (103) and an isoxazole moiety (108) were incorporated as isosteric replacements for the C-6 phenyl moiety (95), resulting in significant improvement in GT-1b and 1a potency. However, the piperazonone class of compounds lacks GT-2 activity and, consequently, were not pursued further into development.
Pharmasset, Inc. 303A College Road East, Princeton, New Jersey 08540, United States.
Ramesh
R
Kakarla
Jian
J
Liu
Devan
D
Naduthambi
Wonsuk
W
Chang
Ralph T
RT
Mosley
Donghui
D
Bao
Holly M Micolochick
HM
Steuer
Meg
M
Keilman
Shalini
S
Bansal
Angela M
AM
Lam
William
W
Seibel
Sandra
S
Neilson
Phillip A
PA
Furman
Michael J
MJ
Sofia
D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D016174:Hepacivirus / Q000187:drug effects*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*
D000998:Antiviral Agents; C080107:NS4B protein, flavivirus; D010879:Piperazines; D017361:Viral Nonstructural Proteins