Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350.
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Raboisson P, de Kock H, Rosenquist A, Nilsson M, Salvador-Oden L, Lin TI, Roue N, Ivanov V, Wahling H, Wickstrom K, Hamelink E, Edlund M, Vrang L, Vendeville S, Van de Vreken W, McGowan D, Tahri A, Hu L, Boutton C, Lenz O, Delouvroy F, Pille G, Surleraux D, Wigerinck P, Samuelsson B, Simmen K
Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350.
Bioorg Med Chem Lett. 2008 Sep 1;18(17):4853-8. doi: 10.1016/j.bmcl.2008.07.088. Epub 2008 Jul 24.
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- 18678486 [ View in PubMed]
- Abstract
SAR analysis performed with a limited set of cyclopentane-containing macrocycles led to the identification of N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl -2,14-dioxo-3,13-diazatricyclo [13.3.0.0(4,6)]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (TMC435350, 32c) as a potent inhibitor of HCV NS3/4A protease (K(i)=0.36nM) and viral replication (replicon EC(50)=7.8nM). TMC435350 also displayed low in vitro clearance and high permeability, which were confirmed by in vivo pharmacokinetic studies. TMC435350 is currently being evaluated in the clinics.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Simeprevir NS3 protease Protein Hepatitis C Virus YesInhibitorDetails Simeprevir NS3/4A protein Protein Hepatitis C Virus YesInhibitorDetails