Discovery of novel non-peptidic ketopiperazine-based renin inhibitors |
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| Authors: | 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 |
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| Institution: | Department of Chemistry, Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor, MI 48105, USA. daniel.holsworth@pfizer.com |
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| Abstract: | 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). |
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