Discovery of novel phosphonate derivatives as hepatitis C virus NS3 protease inhibitors.
A novel class of phosphonate derivatives was designed to mimic the interaction of product-like carboxylate based inhibitors of HCV NS3 protease. A phosphonic acid (compound 2) was demonstrated to be a potent HCV NS3 protease inhibitor, and a potential candidate for treating HCV infection. The syntheses and preliminary biological evaluation of this phosphonate class of inhibitor are described.
Sheng
X Christopher
XC
Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA 94404, USA. csheng@gilead.com
Pyun
Hyung-Jung
HJ
Chaudhary
Kleem
K
Wang
Jianying
J
Doerffler
Edward
E
Fleury
Melissa
M
McMurtrie
Darren
D
Chen
Xiaowu
X
Delaney
William E
WE
Kim
Choung U
CU
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004285:Dogs; D055808:Drug Discovery; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D063065:Organophosphonates; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases