高等学校化学学报 ›› 2000, Vol. 21 ›› Issue (S1): 143.

• Chemistry in Life Sciences • 上一篇    下一篇

Design, Synthesis and Biological Activity of Benzimidazole and Aminophenol Based Factor Xa Inhibitors

ZHAO Zu-Chun (Spring), SHAW Kenneth, ARNAIZ Danny, GRIEDEL Brian, SAKATA Steve, WU Shung, XU Wei, GIULFORD William, LIANG Amy, TRINH Lan, POST Joe, MORRISSEY Michael   

  1. Berlex Laboratories, Inc. 15049 San Pablo Ave. P. O. Box 4099, Richmond, CA 94804-0099, USA
  • 出版日期:2000-12-31 发布日期:2000-12-31

Design, Synthesis and Biological Activity of Benzimidazole and Aminophenol Based Factor Xa Inhibitors

ZHAO Zu-Chun (Spring), SHAW Kenneth, ARNAIZ Danny, GRIEDEL Brian, SAKATA Steve, WU Shung, XU Wei, GIULFORD William, LIANG Amy, TRINH Lan, POST Joe, MORRISSEY Michael   

  1. Berlex Laboratories, Inc. 15049 San Pablo Ave. P. O. Box 4099, Richmond, CA 94804-0099, USA
  • Online:2000-12-31 Published:2000-12-31

摘要:

The serine protease factor Xa (FXa) is a key enzyme in the blood coagulation cascade, acting at the convergent point of the extrinsic and intrinsic pathways. The serine protease factor Xa (FXa) is a key enzyme in the blood coagulation cascade, acting at the convergent point of the extrinsic and intrinsic pathways. In our search for Fxa inhibitors as novel anticoagulants we identified the active isomer of the published FXa inhibitor, 2,7-bis-(4-amidinobenzilidine)-cycloheptan-l-one (BABCH), as the (Z, Z) isomer (ZK-805412, FXa Ki=0.66 nM). This photochemically labile (Z, Z) isomer has served as a conformationally rigid template for the development of distinct classes of potent, selective and orally active FXa inhibitors. Template evolution, in vitro SAR studies as well as our efforts to optimize in vivo parameters will be discussed.

Abstract:

The serine protease factor Xa (FXa) is a key enzyme in the blood coagulation cascade, acting at the convergent point of the extrinsic and intrinsic pathways. The serine protease factor Xa (FXa) is a key enzyme in the blood coagulation cascade, acting at the convergent point of the extrinsic and intrinsic pathways. In our search for Fxa inhibitors as novel anticoagulants we identified the active isomer of the published FXa inhibitor, 2,7-bis-(4-amidinobenzilidine)-cycloheptan-l-one (BABCH), as the (Z, Z) isomer (ZK-805412, FXa Ki=0.66 nM). This photochemically labile (Z, Z) isomer has served as a conformationally rigid template for the development of distinct classes of potent, selective and orally active FXa inhibitors. Template evolution, in vitro SAR studies as well as our efforts to optimize in vivo parameters will be discussed.

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