| Literature DB >> 18954982 |
Sandrine Vendeville1, Magnus Nilsson, Herman de Kock, Tse-I Lin, Dmitry Antonov, Björn Classon, Susana Ayesa, Vladimir Ivanov, Per-Ola Johansson, Pia Kahnberg, Anders Eneroth, Kristina Wikstrom, Lotta Vrang, Michael Edlund, Stefan Lindström, Wim Van de Vreken, David McGowan, Abdellah Tahri, Lili Hu, Oliver Lenz, Frederic Delouvroy, Marleen Van Dooren, Natalie Kindermans, Dominique Surleraux, Piet Wigerinck, Asa Rosenquist, Bertil Samuelsson, Kenneth Simmen, Pierre Raboisson.
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 leading to compound 13Bh, an extremely potent (K(i)=0.1 nM, EC(50)=4.5 nM) and selective (CC(50) (Huh-7 cells)>50 microM) inhibitor, displaying an excellent PK profile in rats characterized by an oral bioavailability of 54% and a high liver exposure after oral administration.Entities:
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Year: 2008 PMID： 18954982 DOI： 10.1016/j.bmcl.2008.10.004
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823