新型非肽类酮哌嗪基肾素抑制剂的发现。
Discovery of novel non-peptidic ketopiperazine-based renin inhibitors.
作者信息
Holsworth Daniel D, Powell Noel A, Downing Dennis M, Cai Cuiman, Cody Wayne L, Ryan J Michael, Ostroski Robert, Jalaie Mehran, Bryant John W, Edmunds Jeremy J
机构信息
Department of Chemistry, Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor, MI 48105, USA.
出版信息
Bioorg Med Chem. 2005 Apr 1;13(7):2657-64. doi: 10.1016/j.bmc.2005.01.048.
Ketopiperazine 2 was designed from a previously published analog. Compound 2 was shown to be a novel, potent inhibitor of renin that, when administered orally, lowered blood pressure in a hypertensive double transgenic (human renin and angiotensinogen) mouse model. Compound 2 was further optimized to sub-nanomolar potency by designing an analog that addressed the S3 sub-pocket of the renin enzyme (16).
酮哌嗪2是根据先前发表的类似物设计的。化合物2被证明是一种新型的、有效的肾素抑制剂，口服给药时可降低高血压双转基因（人肾素和血管紧张素原）小鼠模型的血压。通过设计一种针对肾素酶S3亚口袋的类似物，化合物2的效力进一步优化至亚纳摩尔水平（16）。
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