Design, synthesis, and SAR of cis-1,2-diaminocyclohexane derivatives as potent factor Xa inhibitors. Part I: Exploration of 5-6 fused rings as alternative S1 moieties

被引：29

作者：

Yoshikawa, Kenji ^{[1
]}

Yokomizo, Aki ^{[1
]}

Naito, Hiroyuki ^{[1
]}

Haginoya, Noriyasu ^{[1
]}

Kobayashi, Shozo ^{[2
]}

Yoshino, Toshiharu ^{[1
]}

Nagata, Tsutomu ^{[2
]}

Mochizuki, Akiyoshi ^{[2
]}

Osanai, Ken ^{[1
]}

Watanabe, Kengo ^{[2
]}

Kanno, Hideyuki ^{[3
]}

Ohta, Toshiharu ^{[1
]}

机构：

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

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

[3] Daiichi Sankyo RD Associe Co Ltd, Edogawa Ku, Tokyo 1348630, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 24期

关键词：

Anticoagulant; Factor Xa inhibitor; Food effect; Solubility; DRUG ABSORPTION; ANTICOAGULANTS; DISCOVERY;

D O I：

10.1016/j.bmc.2009.10.023

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：

A series of cis-1,2-diaminocyclohexane derivatives were synthesized with the aim of optimizing previously disclosed factor Xa (fXa) inhibitors. The exploration of 5-6 fused rings as alternative S1 moieties resulted in two compounds which demonstrated improved solubility and reduced food effect compared to the clinical candidate, compound A. Herein, we describe the synthesis and structure-activity relationship (SAR), together with the physicochemical properties and pharmacokinetic (PK) profiles of some prospective compounds. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：8206 / 8220

页数：15

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