Discovery of novel, potent and bioavailable proline-urea based macrocyclic HCV NS3/4A protease inhibitors

…, S Ayesa, V Ivanov, PO Johansson, P Kahnberg…

Index: Vendeville, Sandrine; Nilsson, Magnus; Kock, Herman de; Lin, Tse-I; Antonov, Dmitry; Classon, Bjoern; Ayesa, Susana; Ivanov, Vladimir; Johansson, Per-Ola; Kahnberg, Pia; Eneroth, Anders; Wikstrom, Kristina; Vrang, Lotta; Edlund, Michael; Lindstroem, Stefan; Vreken, Wim Van de; McGowan, David; Tahri, Abdellah; Hu, Lili; Lenz, Oliver; Delouvroy, Frederic; Dooren, Marleen Van; Kindermans, Natalie; Surleraux, Dominique; Wigerinck, Piet; Rosenquist, Asa; Samuelsson, Bertil; Simmen, Kenneth; Raboisson, Pierre Bioorganic and Medicinal Chemistry Letters, 2008 , vol. 18, # 23 p. 6189 - 6193

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Citation Number: 17

Abstract

A novel series of P3-truncated macrocyclic HCV NS3/4A protease inhibitors containing a P2 proline-urea or carbamate scaffold was synthesized. Very potent inhibitors were obtained through the optimization of the macrocycle size, urea and proline substitution, and bioisosteric replacement of the P1 carboxylic acid moiety. Variation of the lipophilicity by introduction of small lipophilic substituents resulted in improved PK profiles, ultimately ...