新型凝血因子Xa抑制剂的设计、合成及生物活性：通过S1和S4配体修饰提高代谢稳定性

Design, synthesis, and biological activity of novel factor Xa inhibitors: improving metabolic stability by S1 and S4 ligand modification.

作者信息

Komoriya Satoshi, Kobayashi Shozo, Osanai Ken, Yoshino Toshiharu, Nagata Tsutomu, Haginoya Noriyasu, Nakamoto Yumi, Mochizuki Akiyoshi, Nagahara Takayasu, Suzuki Makoto, Shimada Takashi, Watanabe Kengo, Isobe Yumiko, Furugoori Taketoshi

机构信息

Tokyo R&D Center, Daiichi Pharmaceutical Co. Ltd, Edogawa-ku, Japan.

出版信息

Bioorg Med Chem. 2006 Mar 1;14(5):1309-30. doi: 10.1016/j.bmc.2005.09.056. Epub 2005 Nov 2.

DOI:10.1016/j.bmc.2005.09.056

PMID:16263291

Abstract

Serine protease factor xa (fXa) inhibitor 1 showed good ex vivo anti-fXa activity upon oral administration in rats. However, it has been revealed that 1 had low metabolic stability against human liver microsomes. To improve the metabolic stability, we attempted to modify the S1 and S4 ligands of 1. These modifications resulted in compound 34b, which exhibited selective anti-fXa activity and excellent anti-coagulation activity.

摘要

丝氨酸蛋白酶因子Xa（fXa）抑制剂1在大鼠口服给药后显示出良好的体外抗fXa活性。然而，已发现1对人肝微粒体的代谢稳定性较低。为了提高代谢稳定性，我们尝试修饰1的S1和S4配体。这些修饰产生了化合物34b，其表现出选择性抗fXa活性和优异的抗凝血活性。