Komoriya Satoshi, Kanaya Naoaki, Nagahara Takayasu, Yokoyama Asako, Inamura Kazue, Yokoyama Yukio, Katakura Shin-ichi, Hara Tsuyoshi
Tokyo R&D Center, Daiichi Pharmaceutical Co. Ltd, 16-13, Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan.
Bioorg Med Chem. 2004 May 1;12(9):2099-114. doi: 10.1016/j.bmc.2004.02.032.
Since factor Xa (fXa) plays a pivotal role in the blood coagulation cascade, inhibition of fXa is thought to be an effective treatment for a variety of thrombotic events. (2S)-2-[4-[[(3S)-1-Acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (DX-9065a) was previously found in our laboratory as a novel orally active factor Xa inhibitor. DX-9065a exhibits a strong inhibitory activity toward fXa by occupying the substrate recognition (called S1) sites and aryl binding sites of fXa. Herein we describe conversions of the amidinonaphthalene and the acetimidoylpyrrolidine moieties of DX-9065a. Some compounds showed remarkably increased in vitro anti-factor Xa and PRCT activities compared with those of DX-9065a. The most promising compound 38 showed four times the prolongation of APTT against DX-9065a after oral administration to rats.
由于凝血因子Xa（fXa）在血液凝固级联反应中起关键作用，抑制fXa被认为是治疗多种血栓形成事件的有效方法。（2S）-2-[4-[[（3S）-1-乙酰亚胺基-3-吡咯烷基]氧基]苯基]-3-（7-脒基-2-萘基）丙酸盐酸盐五水合物（DX-9065a）先前在我们实验室中被发现是一种新型口服活性凝血因子Xa抑制剂。DX-9065a通过占据fXa的底物识别（称为S1）位点和芳基结合位点，对fXa表现出强大的抑制活性。在此我们描述了DX-9065a的脒基萘和乙酰亚胺基吡咯烷部分的转化。与DX-9065a相比，一些化合物在体外表现出显著增强的抗凝血因子Xa活性和PRCT活性。最有前景的化合物38在对大鼠口服给药后，其活化部分凝血活酶时间（APTT）延长倍数是DX-9065a的四倍。
