2. Academic Validation
  3. 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

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

Affiliation

  • 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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