title: Investigation of the mode of binding of a novel series of N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamides to the hepatitis C virus polymerase.
abstract: Structure based rationales for the activities of potent N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamide inhibitors of the hepatitis C viral polymerase are described herein. These compounds bind to the hepatitis C virus non-structural protein 5B (NS5B), and co-crystal structures of select examples from this series with NS5B are reported. Comparison of co-crystal structures of a potent analog with both NS5B genotype 1a and genotype 1b provides a possible explanation for the genotype-selectivity observed with this compound class and suggests opportunities for the further optimization of the series.
authors: Bristol Myers Squibb, Chemical and Protein Technologies, Wallingford, CT 06492, United States. robert.gentles@bms.com
authors: Robert G
authors: RG
authors: Gentles
authors: Steven
authors: S
authors: Sheriff
authors: Brett R
authors: BR
authors: Beno
authors: Changhong
authors: C
authors: Wan
authors: Kevin
authors: K
authors: Kish
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: Mark R
authors: MR
authors: Witmer
authors: Paul
authors: P
authors: Morin
authors: Ying-Kai
authors: YK
authors: Wang
authors: Karen
authors: K
authors: Rigat
authors: Julie
authors: J
authors: Lemm
authors: Stacey
authors: S
authors: Voss
authors: Mengping
authors: M
authors: Liu
authors: Lenore
authors: L
authors: Pelosi
authors: Susan B
authors: SB
authors: Roberts
authors: Min
authors: M
authors: Gao
authors: John F
authors: JF
authors: Kadow
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000577:Amides; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase