Quan M L, Wexler R R
DuPont Pharmaceuticals Company, Experimental Station, Wilmington, DE 19880-0500, USA.
Curr Top Med Chem. 2001 Jun;1(2):137-49. doi: 10.2174/1568026013395407.
Thrombosis is a major cause of mortality in the industrialized world. Therefore, the control of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (fXa), the enzyme directly responsible for thrombin generation. In this review we describe our approaches in the design and synthesis of small molecule, noncovalent fXa inhibitors. Rational drug design and selective screening of our GPIIb/IIIa library afforded several lead compounds for our fXa program. Following-up the leads in the isoxazoline series led to potent fXa inhibitors such as SF303 and SK509 with only one basic group. The isoxazole series was then designed to remove the chiral center in the isoxazoline ring, and this effort led to SA862 which has subnanomolar fXa affinity. Optimizing the core structure generated a series of novel five-membered ring heterocycles substituted with benzamidine, which are potent fXa inhibitors. Further optimization in the pyrazole series resulted in the discovery of fXa inhibitors such as SN429 with picomolar fXa affinity. Efforts to improve the oral bioavailability by lowering the basicity of these compounds, while simultaneously maintaining potency against fXa, culminated in the discovery of DPC 423. DPC 423 was selected for clinical evaluation as a potent and orally bioavailable fXa inhibitor.
在工业化国家，血栓形成是导致死亡的主要原因。因此，控制血液凝固已成为新型治疗药物的主要靶点。一种有吸引力的方法是抑制Xa因子（fXa），该酶直接负责凝血酶的生成。在本综述中，我们描述了设计和合成小分子非共价fXa抑制剂的方法。通过合理的药物设计和对我们的糖蛋白IIb/IIIa文库进行选择性筛选，为我们的fXa项目提供了几种先导化合物。对异恶唑啉系列中的先导化合物进行跟进，得到了仅含一个碱性基团的强效fXa抑制剂，如SF303和SK509。然后设计异恶唑系列以去除异恶唑啉环中的手性中心，这一努力得到了对fXa具有亚纳摩尔亲和力的SA862。对核心结构进行优化产生了一系列被苯甲脒取代的新型五元环杂环化合物，它们都是强效fXa抑制剂。对吡唑系列进行进一步优化，发现了对fXa具有皮摩尔亲和力的fXa抑制剂，如SN429。通过降低这些化合物的碱性来提高口服生物利用度，同时保持对fXa的效力，最终发现了DPC 423。DPC 423被选为一种强效且口服生物可利用的fXa抑制剂进行临床评估。
