Clark Charles G, Rossi Karen A, Corte James R, Fang Tianan, Smallheer Joanne M, De Lucca Indawati, Nirschl David S, Orwat Michael J, Pinto Donald J P, Hu Zilun, Wang Yufeng, Yang Wu, Jeon Yoon, Ewing William R, Myers Joseph E, Sheriff Steven, Lou Zhen, Bozarth Jeffrey M, Wu Yiming, Rendina Alan, Harper Timothy, Zheng Joanna, Xin Baomin, Xiang Qian, Luettgen Joseph M, Seiffert Dietmar A, Wexler Ruth R, Lam Patrick Y S
Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ 08543, United States.
Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ 08543, United States.
Bioorg Med Chem Lett. 2019 Oct 1;29(19):126604. doi: 10.1016/j.bmcl.2019.08.008. Epub 2019 Aug 16.
This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9. These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency.
本手稿描述了一系列具有口服生物利用度的FXIa大环抑制剂的发现。在基于结构的药物设计和配体结合的X射线晶体结构的辅助下，连接P1部分与大环核心的基团进行了修饰，目的是减少氢键供体以改善相对于9的药代动力学性能。这项工作导致发现了几种环状P1连接体，以10为例，它们是9的丙烯酰胺连接体所展示的生物活性构象的受限模拟物。这些环状P1连接体表现出增强的生物利用度和提高的效力。
