Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 21, Issue 18, Pages 5907-5922Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2013.06.057
Keywords
Hypertension; Renin; Piperidine; Ketopiperazine
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We report synthesis and optimization of a series of (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as renin inhibitors. Chemical modification of P-1', P-2' and P-3 portions led to a promising 3,5-disubstituted piperidine 32o showing high renin inhibitory activity and favorable oral exposure in both rats and cynomolgus monkeys with acceptable CYP and hERG current inhibition. Compound 32o exhibited a significant blood pressure lowering effect by oral administration in two hypertensive animal models, double transgenic rats and furosemide pretreated cynomolgus monkeys. (C) 2013 Elsevier Ltd. All rights reserved.
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