Renin inhibitors for the treatment of hypertension: design and optimization of a novel series of spirocyclic piperidines.

Abstract

The discovery and SAR of a novel series of spirocyclic renin inhibitors are described herein. It was found that by restricting the northern aromatic plate to the bioactive conformation through spirocyclization, increase in renin potency and decrease in hERG affinity could both be realized. When early members of this series were found to be potent time-dependent CYP3A4 inhibitors, two distinct strategies to address this liability were explored and this effort culminated in the identification of compound 31 as an optimized renin inhibitor.

• Authors: Austin Chen, Renee Aspiotis, Louis-Charles Campeau, Elizabeth Cauchon, Amadine Chefson, Yves Ducharme, Jean-Pierre Falgueyret, Sébastien Gagné, Yongxin Han, Robert Houle, Sébastien Laliberté, Guillaume Larouche, Jean-François Lévesque, Dan McKay, David Percival
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 24 Pg. 7399-404 (Dec 15 2011) ISSN: 1464-3405 [Electronic] England
• PMID: 22071301 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Antihypertensive Agents
• Cytochrome P-450 CYP3A Inhibitors
• Piperidines
• Protease Inhibitors
• Spiro Compounds
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human
• Renin

Topics

• Animals
• Antihypertensive Agents (chemistry, pharmacokinetics, therapeutic use)
• Binding Sites
• Catalytic Domain
• Computer Simulation
• Cytochrome P-450 CYP3A (metabolism)
• Cytochrome P-450 CYP3A Inhibitors
• Dogs
• Drug Design
• Humans
• Hypertension (drug therapy)
• Macaca mulatta
• Piperidines (chemistry, pharmacokinetics, therapeutic use)
• Protease Inhibitors (chemistry, pharmacokinetics, therapeutic use)
• Rats
• Renin (antagonists & inhibitors, metabolism)
• Spiro Compounds (chemistry)
• Structure-Activity Relationship