Author/Authors :
Sandrine Vendeville، نويسنده , , Magnus Nilsson، نويسنده , , Herman de Kock، نويسنده , , Tse-I Lin، نويسنده , , Dmitry Antonov، نويسنده , , Bj?rn Classon، نويسنده , , Susana Ayesa، نويسنده , , Vladimir Ivanov، نويسنده , , Per-Ola Johansson، نويسنده , , Pia Kahnberg، نويسنده , , Anders Eneroth، نويسنده , , Kristina Wikstrom، نويسنده , , Lotta Vrang، نويسنده , , Michael Edlund، نويسنده , , Stefan Lindstr?m، نويسنده , , Wim Van de Vreken، نويسنده , , David McGowan، نويسنده , , Abdellah Tahri، نويسنده , , Lili Hu، نويسنده , , Oliver Lenz، نويسنده , , et al.، نويسنده ,
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 (Ki = 0.1 nM, EC50 = 4.5 nM) and selective (CC50 (Huh-7 cells) > 50 μM) inhibitor, displaying an excellent PK profile in rats characterized by an oral bioavailability of 54% and a high liver exposure after oral administration.
Keywords :
Hepatitis C , Serine protease , Macrocycle , NS3
