Pruitt James R, Pinto Donald J P, Galemmo Robert A, Alexander Richard S, Rossi Karen A, Wells Brian L, Drummond Spencer, Bostrom Lori L, Burdick Debra, Bruckner Robert, Chen Haiying, Smallwood Angela, Wong Pancras C, Wright Matthew R, Bai Steven, Luettgen Joseph M, Knabb Robert M, Lam Patrick Y S, Wexler Ruth R
Bristol-Myers Squibb Company, Pharmaceutical Research Institute, 31 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, USA.
J Med Chem. 2003 Dec 4;46(25):5298-315. doi: 10.1021/jm030212h.
Factor Xa, a serine protease, is at the critical juncture between the intrinsic and extrinsic pathways of the coagulation cascade. Inhibition of factor Xa has the potential to provide effective treatment for both venous and arterial thrombosis. We recently described a series of meta-substituted phenylpyrazoles that are highly potent, selective, and orally bioavailable factor Xa inhibitors. In this paper we report our efforts to further optimize the selectivity profile of our factor Xa inhibitors with a series of ortho- and/or para-substituted phenylpyrazole derivatives. The most potent compounds display sub-nanomolar inhibition constants for factor Xa and show greater than 1000-fold selectivity against other serine proteases. These compounds are also effective in a rabbit model of arteriovenous shunt thrombosis. Optimization of this series led to the preclinical development of DPC602, a 2-(aminomethyl)phenylpyrazole analogue, as a highly potent, selective, and orally bioavailable factor Xa inhibitor.
凝血因子Xa是一种丝氨酸蛋白酶，处于凝血级联反应内源性和外源性途径的关键节点。抑制凝血因子Xa有可能为静脉和动脉血栓形成提供有效的治疗方法。我们最近描述了一系列间位取代的苯基吡唑，它们是高效、选择性且口服生物利用度高的凝血因子Xa抑制剂。在本文中，我们报告了我们为通过一系列邻位和/或对位取代的苯基吡唑衍生物进一步优化凝血因子Xa抑制剂的选择性概况所做的努力。最有效的化合物对凝血因子Xa显示出亚纳摩尔级的抑制常数，并且对其他丝氨酸蛋白酶表现出大于1000倍的选择性。这些化合物在动静脉分流血栓形成的兔模型中也有效。对该系列化合物的优化导致了2-(氨基甲基)苯基吡唑类似物DPC602的临床前开发，它是一种高效、选择性且口服生物利用度高的凝血因子Xa抑制剂。
