title: SAR studies on a series of N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamides: potent inhibitors of the polymerase enzyme (NS5B) of the hepatitis C virus.
abstract: Described herein is the initial optimization of (+/-) N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamide (1), a hit discovered in a high throughput screen run against the NS5B polymerase enzyme of the hepatitis C virus. This effort resulted in the identification of (S)-N-sec-butyl-6-((R)-3-(4-(trifluoromethoxy)benzylcarbamoyl)-4-(4-(trifluoromethoxy)phenylsulfonyl)piperazin-1-yl)pyridazine-3-carboxamide (2), that displayed potent replicon activities against HCV genotypes 1b and 1a (EC(50) 1b/1a=7/89 nM).
authors: Bristol Myers Squibb, Chemical and Protein Technologies, Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. robert.gentles@bms.com
authors: Robert G
authors: RG
authors: Gentles
authors: Min
authors: M
authors: Ding
authors: Xiaofan
authors: X
authors: Zheng
authors: Louis
authors: L
authors: Chupak
authors: Michael A
authors: MA
authors: Poss
authors: Brett R
authors: BR
authors: Beno
authors: Lenore
authors: L
authors: Pelosi
authors: Mengping
authors: M
authors: Liu
authors: Julie
authors: J
authors: Lemm
authors: Ying-Kai
authors: YK
authors: Wang
authors: Susan
authors: S
authors: Roberts
authors: Min
authors: M
authors: Gao
authors: John
authors: J
authors: Kadow
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D000077489:Piperazine; D010879:Piperazines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase