Title of article :
Design, synthesis and biological activity of YM-60828 derivatives: potent and orally-Bioavailable factor Xa inhibitors based on naphthoanilide and naphthalensulfonanilide templates Original Research Article
Author/Authors :
Fukushi Hirayama، نويسنده , , Hiroyuki Koshio، نويسنده , , Tsukasa Ishihara، نويسنده , , Susumu Watanuki، نويسنده , , Shunichiro Hachiya، نويسنده , , Hiroyuki Kaizawa، نويسنده , , Takahiro Kuramochi، نويسنده , , Naoko Katayama، نويسنده , , Hiroyuki Kurihara، نويسنده , , Yuta Taniuchi، نويسنده , , Kazuo Sato، نويسنده , , Yumiko Sakai-Moritani، نويسنده , , Seiji Kaku، نويسنده , , Tomihisa Kawasaki، نويسنده , , Yuzo Matsumoto، نويسنده , , Shuichi Sakamoto، نويسنده , , Shin-ichi Tsukamoto، نويسنده ,
Abstract :
Factor Xa (FXa) is a serine protease which plays a pivotal role in the coagulation cascade. The inhibition of FXa has received great interest as a potential target for the development of new antithrombotic drug. Herein we describe a series of novel 7-amidino-2-naphthoanilide and 7-amidino-2-naphthalensulfonanilide derivatives which are potent FXa inhibitors. These scaffolds are rigid and are allowed to adopt an L-shape conformation which was estimated as the active conformation based on a docking study of YM-60828 with FXa. Optimization of the side chain at the central aniline nitrogen of 7-amidino-2-naphthoanilide has led to several potent and orally active FXa inhibitors. 5h (YM-169964), the best compound of these series, showed potent FXa inhibitory activity (IC50=3.9 nM) and effectively prolonged prothrombin time by 9.6-fold ex vivo at an oral dose of 3 mg/kg in squirrel monkeys.
