Merck & Co., Inc., Kenilworth, NJ 07033, United States.
Merck & Co., Inc., Kenilworth, NJ 07033, United States.
Bioorg Med Chem Lett. 2020 Aug 15;30(16):127072. doi: 10.1016/j.bmcl.2020.127072. Epub 2020 Feb 29.
A series of 4, 4-disubstituted proline analogs were designed, synthesized, and tested for selective inhibition of blood coagulation factor XIa in search of new non-vitamin K antagonists based oral anticoagulants for potential prevention and treatment of thrombotic diseases. Starting from a potent thrombin (FIIa) inhibitor chemotype with FIIa IC = 1 nM and FXIa IC = 160 nM, medicinal chemistry iterations guided by molecular modeling and structure-based drug design led to steady improvement of FXIa potency while dialing down thrombin activity and improving selectivity. Through this exercise, a thousand-fold enhancement of selectivity over thrombin was achieved with some analogs carrying factor XIa inhibition potencies in the 10 nM range. In this communication, we discuss the design principles and structure activity relationship (SAR) of these novel FXIa selective inhibitors.
设计、合成并测试了一系列 4,4-二取代脯氨酸类似物，以寻找新型非维生素 K 拮抗剂口服抗凝剂，用于潜在的血栓性疾病的预防和治疗。从一种强效凝血酶（FIIa）抑制剂化学型开始，其对 FIIa 的 IC50 为 1 nM，对 FXIa 的 IC50 为 160 nM，通过分子模拟和基于结构的药物设计指导的药物化学迭代，使 FXIa 的效力不断提高，同时降低了凝血酶的活性并提高了选择性。通过这种方法，一些类似物对凝血酶的选择性提高了千倍，其对 FXIa 的抑制作用达到了 10 nM 范围。在本通讯中，我们讨论了这些新型 FXIa 选择性抑制剂的设计原则和结构活性关系（SAR）。
