Center for Drug Discovery, College of Pharmacy, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
Bioorg Med Chem. 2011 Jul 15;19(14):4238-49. doi: 10.1016/j.bmc.2011.05.059. Epub 2011 Jun 1.
Eighteen octane-carboxamide based renin inhibitors with extended segments for mimicking P3' unit of angiotensinogen have been synthesized. The biological evaluation identified novel renin inhibitors with more potent activity than aliskiren. Molecular docking studies showed that the extended amide-tails matched the P3' position of angiotensinogen and exerted interactions with the S3' site of renin. An unexpected π-π stacking interaction was observed during docking study for compound 9r, which could be a reasonable explanation for the outstanding potency of this compound. Further study is in progress to reveal a feasibility for developing novel renin inhibitors based on the possible non-classical interactions between the ligands and the new subsite of renin.
已经合成了十八种基于辛烷酰胺的肾素抑制剂，这些抑制剂具有扩展片段，用于模拟血管紧张素原的 P3' 单位。生物学评价确定了具有比阿利克仑更强活性的新型肾素抑制剂。分子对接研究表明，扩展的酰胺尾巴与血管紧张素原的 P3' 位置匹配，并与肾素的 S3' 位点相互作用。在对接研究中观察到化合物 9r 出现了意想不到的π-π堆积相互作用，这可以合理地解释该化合物的出色效力。进一步的研究正在进行中，以揭示基于配体与肾素新亚基之间可能存在的非经典相互作用，开发新型肾素抑制剂的可行性。
