Discovery of N-[(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-(dimethylcarbamoyl) cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride: A novel, potent and orally active direct inhibitor of factor Xa

被引：39

作者：

Nagata, Tsutomu ^{[1
]}

Yoshino, Toshiharu ^{[2
]}

Haginoya, Noriyasu ^{[2
]}

Yoshikawa, Kenji ^{[2
]}

Nagamochi, Masatoshi ^{[2
]}

Kobayashi, Syozo ^{[2
]}

Komoriya, Satoshi ^{[2
]}

Yokomizo, Aki ^{[2
]}

Muto, Ryo ^{[1
]}

Yamaguchi, Mitsuhiro ^{[1
]}

Osanai, Ken ^{[1
]}

Suzuki, Makoto ^{[2
]}

Kanno, Hideyuki ^{[3
]}

机构：

[1] Daiichi Sankyo Co Ltd, R&D Div, Shinagawa Ku, Tokyo 1408710, Japan

[2] Daiichi Sankyo Co Ltd, R&D Div, Edogawa Ku, Tokyo 1348630, Japan

[3] Daiichi Sankyo RD Associe Co Ltd, Shinagawa Ku, Tokyo 1408710, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 03期

关键词：

Factor Xa inhibitors; Anticoagulant; Non-amidino compound; Oral bioavailability; Protein binding; Lipophilicity; DX-9065A; ANTICOAGULANT; DERIVATIVES;

D O I：

10.1016/j.bmc.2008.12.037

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

In the early 1990's, we reported on the low-molecular selective fXa inhibitor DX-9065a having two amidino groups. However, it had poor oral bioavailability due to its strong basic amidino groups. To obtain fXa inhibitors with improved oral bioavailability, we investigated various non-amidino fXa inhibitors and finally discovered cis-1,2-diaminocyclohexane derivative 4c to have potent fXa inhibition, promising anticoagulant activity, and good oral bioavailability, compared with amidino compound DX-9065a. In addition, we will discuss the influence of the third substituent on the cyclohexane ring on anti-fXa activity, anticoagulant activity, PK profile, and lipophilicity. (c) 2008 Elsevier Ltd. All rights reserved.

引用

页码：1193 / 1206

页数：14

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