Author/Authors :
Fukushi Hirayama، نويسنده , , Hiroyuki Koshio، نويسنده , , Naoko Katayama، نويسنده , , Tsukasa Ishihara، نويسنده , , Hiroyuki Kaizawa، نويسنده , , Yuta Taniuchi، نويسنده , , Kazuo Sato، نويسنده , , Yumiko Sakai-Moritani، نويسنده , , Seiji Kaku، نويسنده , , Hiroyuki Kurihara، نويسنده , , Tomihisa Kawasaki، نويسنده , , Yuzo Matsumoto، نويسنده , , Shuichi Sakamoto، نويسنده , , Shin-ichi Tsukamoto، نويسنده ,
Abstract :
Compound YM-60828 was previously characterized in our laboratory as a potent, selective and orally-bioavailable Factor Xa (FXa) inhibitor. The L-shape conformation of this compound in the active site of FXa was recognized as an important factor in displaying its FXa inhibitory activity. This led to the exploration of conformationally restricted cyclic scaffolds bearing a similar active conformation. The current study investigated a novel series of benzothiadiazine-4-one based compounds as FXa inhibitors. Structure–activity relationship (SAR) investigations revealed some potent FXa inhibitors that were selected for further in vitro and ex vivo anticoagulant studies. Among them, compound 6j (YM-169920) was proved to be most effective anticoagulant in this series. The synthesis and SAR in addition to docking studies of this class of inhibitors are described.
