基于酮哌嗪的肾素抑制剂：“C”环的优化。
Ketopiperazine-based renin inhibitors: optimization of the "C" ring.
作者信息
Holsworth Daniel D, Cai Cuiman, Cheng Xue-Min, Cody Wayne L, Downing Dennis M, Erasga Noe, Lee Chitase, Powell Noel A, Edmunds Jeremy J, Stier Michael, Jalaie Mehran, Zhang Erli, McConnell Pat, Ryan Michael J, Bryant John, Li Tingsheng, Kasani Aparna, Hall Eric, Subedi Rajendra, Rahim Mohammad, Maiti Samarendra
机构信息
Pfizer Global Research and Development, Michigan Laboratories, Department of Chemistry, Ann Arbor, MI 48105, USA.
出版信息
Bioorg Med Chem Lett. 2006 May 1;16(9):2500-4. doi: 10.1016/j.bmcl.2006.01.084. Epub 2006 Feb 15.
A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's < or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.
对S3亚口袋活性要求进行了系统研究。观察到，对于最佳肾素抑制作用，S3亚口袋中线性且空间位阻小的侧链取代基是优选的。S3亚口袋中的极性基团耐受性不佳，会导致肾素抑制活性降低。此外，clog P值≤3的化合物表现出CYP3A4抑制活性显著降低。
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