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

被引：21

作者：

Vendeville, Sandrine ^{[1
]}

Nilsson, Magnus ^{[2
]}

de Kock, Herman ^{[1
]}

Lin, Tse-I ^{[1
]}

Antonov, Dmitry ^{[2
]}

Classon, Bjorn ^{[2
]}

Ayesa, Susana ^{[2
]}

Ivanov, Vladimir ^{[2
]}

Johansson, Per-Ola ^{[2
]}

Kahnberg, Pia ^{[2
]}

Eneroth, Anders ^{[2
]}

Wikstrom, Kristina ^{[2
]}

Vrang, Lotta ^{[2
]}

Edlund, Michael ^{[2
]}

Lindstrom, Stefan ^{[2
]}

Van de Vreken, Wim ^{[1
]}

McGowan, David ^{[1
]}

Tahri, Abdellah ^{[1
]}

Hua, Lili ^{[1
]}

Lenz, Oliver ^{[1
]}

Delouvroy, Frederic ^{[1
]}

Van Dooren, Marleen ^{[1
]}

Kindermans, Natalie ^{[1
]}

Surleraux, Dominique ^{[1
]}

Wigerinck, Piet ^{[1
]}

Rosenquist, Asa ^{[2
]}

Samuelsson, Bertil ^{[2
]}

Simmen, Kenneth ^{[1
]}

Raboisson, Pierre ^{[1
]}

机构：

[1] Tibotec BVBA, B-2800 Mechelen, Belgium

[2] Medivir AB, SE-14122 Huddinge, Sweden

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 23期

关键词：

Hepatitis C; Serine protease; Macrocycle; NS3;

D O I：

10.1016/j.bmcl.2008.10.004

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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, EC50 = 4.5 nM) and selective (CC50 (Huh-7 cells) > 50 mu M) inhibitor, displaying an excellent PK pro. le in rats characterized by an oral bioavailability of 54% and a high liver exposure after oral administration. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：6189 / 6193

页数：5

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