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

Abstract

An SAR campaign aimed at decreasing the overall lipophilicity of renin inhibitors such as 1 is described herein. It was found that replacement of the northern appendage in 1 with an N-methyl pyridone and subsequent re-optimization of the benzyl amide handle afforded compounds with in vitro and in vivo profiles suitable for further profiling. An unexpected CV toxicity in dogs observed with compound 20 led to the employment of a time and resource sparing rodent model for in vivo screening of key compounds. This culminated in the identification of compound 31 as an optimized renin inhibitor.

• Authors: Austin Chen, Louis-Charles Campeau, Elizabeth Cauchon, Amandine Chefson, Yves Ducharme, Daniel Dubé, Jean-Pierre Falgueyret, Pierre-André Fournier, Sébastien Gagné, Erich Grimm, Yongxin Han, Robert Houle, Jing-Qi Huang, Patrick Lacombe, Sébastien Laliberté, Jean-François Lévesque, Susana Liu, Dwight MacDonald, Bruce Mackay, Dan McKay, M David Percival, Chris Regan, Hillary Regan, René St-Jacques, Sylvie Toulmond
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 13 Pg. 3970-5 (Jul 01 2011) ISSN: 1464-3405 [Electronic] England
• PMID: 21621998 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Piperidines
• Pyridones
• Renin

Topics

• Animals
• Dogs
• Drug Design
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Hypertension (drug therapy)
• Inhibitory Concentration 50
• Models, Molecular
• Molecular Structure
• Piperidines (chemical synthesis, chemistry, therapeutic use)
• Pyridones (chemical synthesis, chemistry, therapeutic use)
• Rats
• Renin (antagonists & inhibitors)
• Structure-Activity Relationship