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.
Pierre Raboisson  1 ,  Herman de Kock ,  Asa Rosenquist ,  Magnus Nilsson ,  Lourdes Salvador-Oden ,  Tse-I Lin ,  Natalie Roue ,  Vladimir Ivanov ,  Horst Wähling ,  Kristina Wickström ,  Elizabeth Hamelink ,  Michael Edlund ,  Lotta Vrang ,  Sandrine Vendeville ,  Wim Van de Vreken ,  David McGowan ,  Abdellah Tahri ,  Lili Hu ,  Carlo Boutton ,  Oliver Lenz ,  Frederic Delouvroy ,  Geert Pille ,  Dominique Surleraux ,  Piet Wigerinck ,  Bertil Samuelsson ,  Kenneth Simmen
Affiliations
  • 1. Tibotec BVBA, Gen. De Wittelaan L11 B3, B-2800 Mechelen, Belgium.
PMID: 18678486 DOI: 10.1016/j.bmcl.2008.07.088
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.

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