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
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
复制标题
DOI：
10.1016/j.bmc.2008.12.037
复制
发表时间：
2009-02-01
影响因子：
3.5
通讯作者：
Kanno, Hideyuki
中科院分区：
文献类型：
--
作者：
Nagata, Tsutomu;Yoshino, Toshiharu;Kanno, Hideyuki
在20世纪90年代早期，我们报道了具有两个脒基的低分子选择性fXa抑制剂DX-9065 a。然而，由于其强碱性脒基，其口服生物利用度较差。为了获得具有改善的口服生物利用度的fXa抑制剂，我们研究了各种非脒基fXa抑制剂，并最终发现与脒基化合物DX-9065 a相比，顺式-1，2-二氨基环己烷衍生物4c具有有效的fXa抑制、有希望的抗凝活性和良好的口服生物利用度。此外，我们将讨论环己烷环上的第三个取代基对抗fXa活性、抗凝活性、PK特征和亲脂性的影响。(c)2008爱思唯尔有限公司保留所有权利。
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.