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

S Komoriya, S Kobayashi, K Osanai, T Yoshino…

Index: 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 Bioorganic and Medicinal Chemistry, 2006 , vol. 14, # 5 p. 1309 - 1330

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Citation Number: 34

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.