221161-00-8Relevant articles and documents
Design, synthesis and biological activity of YM-60828 derivatives: Potent and orally-bioavailable factor Xa inhibitors based on naphthoanilide and naphthalensulfonanilide templates
Hirayama, Fukushi,Koshio, Hiroyuki,Ishihara, Tsukasa,Watanuki, Susumu,Hachiya, Shunichiro,Kaizawa, Hiroyuki,Kuramochi, Takahiro,Katayama, Naoko,Kurihara, Hiroyuki,Taniuchi, Yuta,Sato, Kazuo,Sakai-Moritani, Yumiko,Kaku, Seiji,Kawasaki, Tomihisa,Matsumoto, Yuzo,Sakamoto, Shuichi,Tsukamoto, Shin-ichi
, p. 2597 - 2610 (2007/10/03)
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.
