Abstract
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 P1', P2' and P3 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.
Keywords:
Hypertension; Ketopiperazine; Piperidine; Renin.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Amides / chemistry*
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Amides / pharmacokinetics
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Amides / therapeutic use
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Animals
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Blood Pressure / drug effects
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Disease Models, Animal
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Furosemide / pharmacology
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Half-Life
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Hypertension / drug therapy
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Macaca fascicularis
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Piperazines / chemical synthesis*
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Piperazines / pharmacokinetics
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Piperazines / therapeutic use
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Piperidines / chemical synthesis*
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Piperidines / chemistry*
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Piperidines / pharmacokinetics
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Piperidines / therapeutic use
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / pharmacokinetics
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Protease Inhibitors / therapeutic use
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Rats
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Rats, Transgenic
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Renin / antagonists & inhibitors*
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Renin / metabolism
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Structure-Activity Relationship
Substances
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(3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamide
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Amides
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Piperazines
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Piperidines
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Protease Inhibitors
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piperidine
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Furosemide
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Renin