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Ketopiperazine-based renin inhibitors: optimization of the "C" ring |
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| Authors: | 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 |
| Affiliation: | Pfizer Global Research and Development, Michigan Laboratories, Department of Chemistry, Ann Arbor, MI 48105, USA. Daniel.Holsworth@pfizer.com |
| Abstract: | 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. |
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