Abstract
The discovery and SAR of a series of potent renin inhibitors possessing a novel 3,4-diarylpiperidine scaffold are described herein. The resulting compound 38 exhibit low nanomolar plasma renin IC(50), had a clean CYP 3A4 profile and displayed micromolar affinity for the hERG channel. Furthermore, it was found to be efficacious in the double transgenic rat hypertension model and show good to moderate oral bioavailability in two animal species.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Antihypertensive Agents / chemistry*
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Antihypertensive Agents / pharmacokinetics
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Antihypertensive Agents / pharmacology
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Antihypertensive Agents / therapeutic use*
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Biological Availability
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Cytochrome P-450 CYP3A / metabolism
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Cytochrome P-450 CYP3A Inhibitors
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Dogs
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Ether-A-Go-Go Potassium Channels / metabolism
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Humans
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Hypertension / drug therapy*
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Piperidines / chemistry*
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Piperidines / pharmacokinetics
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Piperidines / pharmacology
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Piperidines / therapeutic use*
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Rats
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Rats, Sprague-Dawley
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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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Antihypertensive Agents
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Cytochrome P-450 CYP3A Inhibitors
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Ether-A-Go-Go Potassium Channels
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Piperidines
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Cytochrome P-450 CYP3A
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Renin