Shi Yan, Sitkoff Doree, Zhang Jing, Han Wei, Hu Zilun, Stein Philip D, Wang Ying, Kennedy Lawrence J, O'Connor Stephen P, Ahmad Saleem, Liu Eddie C-K, Seiler Steve M, Lam Patrick Y S, Robl Jeffrey A, Macor John E, Atwal Karnail S, Zahler Robert
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08543-5400, USA.
Bioorg Med Chem Lett. 2007 Nov 1;17(21):5952-8. doi: 10.1016/j.bmcl.2007.07.063. Epub 2007 Aug 21.
The design and synthesis of a novel class of amino(methyl) pyrrolidine-based sulfonamides as potent and selective FXa inhibitors is reported. The amino(methyl) pyrrolidine scaffolds were designed based on the proposed bioisosterism to the piperazine core in known FXa inhibitors. The SAR study led to compound 15 as the most potent FXa inhibitor in this series, with an IC(50) of 5.5 nM and PT EC(2x) of 1.7 microM. The proposed binding models show that the pyrrolidine cores are in van der Waals contact with the enzyme surface, and the flexibility of amino(methyl) pyrrolidines allows the two nitrogen atoms to anchor both the P1 and P4 groups to fit similarly in the S1 and S4 pockets.
报道了一类新型基于氨基（甲基）吡咯烷的磺酰胺作为强效和选择性凝血因子Xa（FXa）抑制剂的设计与合成。基于已知FXa抑制剂中哌嗪核心的拟生物电子等排体设计了氨基（甲基）吡咯烷支架。构效关系（SAR）研究得出化合物15为本系列中最有效的FXa抑制剂，其半数抑制浓度（IC50）为5.5 nM，血浆凝血酶原时间（PT）有效浓度（EC2x）为1.7 μM。所提出的结合模型表明，吡咯烷核心与酶表面存在范德华接触，并且氨基（甲基）吡咯烷的灵活性使得两个氮原子能够锚定P1和P4基团，从而类似地适配于S1和S4口袋。
