Ye Bin, Arnaiz Damian O, Chou Yuo-Ling, Griedel Brian D, Karanjawala Rushad, Lee Wheeseong, Morrissey Michael M, Sacchi Karna L, Sakata Steven T, Shaw Kenneth J, Wu Shung C, Zhao Zuchun, Adler Marc, Cheeseman Sarah, Dole William P, Ewing Janice, Fitch Richard, Lentz Dao, Liang Amy, Light David, Morser John, Post Joseph, Rumennik Galina, Subramanyam Babu, Sullivan Mark E, Vergona Ron, Walters Janette, Wang Yi-Xin, White Kathy A, Whitlow Marc, Kochanny Monica J
Berlex Biosciences, Post Office Box 4099, Richmond, California 94804-0099, USA.
J Med Chem. 2007 Jun 28;50(13):2967-80. doi: 10.1021/jm070125f. Epub 2007 May 31.
There remains a high unmet medical need for a safe oral therapy for thrombotic disorders. The serine protease factor Xa (fXa), with its central role in the coagulation cascade, is among the more promising targets for anticoagulant therapy and has been the subject of intensive drug discovery efforts. Investigation of a hit from high-throughput screening identified a series of thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead optimization by incorporation of hydrophilic groups led to the discovery of compounds with picomolar inhibitory potency and micromolar in vitro anticoagulant activity. Based on their high potency, selectivity, oral pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced into development.
对于血栓性疾病的安全口服疗法，仍存在未满足的高度医疗需求。丝氨酸蛋白酶因子Xa（fXa）在凝血级联反应中起核心作用，是抗凝治疗中较有前景的靶点之一，并且一直是药物研发密集努力的对象。对高通量筛选中发现的一个活性化合物的研究确定了一系列噻吩取代的邻氨基苯甲酰胺作为有效的非脒类fXa抑制剂。通过引入亲水性基团进行先导化合物优化，发现了具有皮摩尔抑制效力和微摩尔体外抗凝活性的化合物。基于它们在大鼠静脉血栓形成淤滞模型中的高效力、选择性、口服药代动力学和疗效，化合物ZK 814048（10b）、ZK 810388（13a）和ZK 813039（17m）进入了开发阶段。
