Design and optimization of new piperidines as renin inhibitors

Olivier Corminboeuf; Olivier Bezençon; Corinna Grisostomi; Luboš Remeň; Sylvia Richard-Bildstein; Daniel Bur; Lars Prade; Patrick Hess; Panja Strickner; Walter Fischli; Beat Steiner; Alexander Treiber

doi:10.1016/j.bmcl.2010.08.086

Design and optimization of new piperidines as renin inhibitors

Bioorg Med Chem Lett. 2010 Nov 1;20(21):6286-90. doi: 10.1016/j.bmcl.2010.08.086. Epub 2010 Aug 22.

Authors

Olivier Corminboeuf¹, Olivier Bezençon, Corinna Grisostomi, Luboš Remeň, Sylvia Richard-Bildstein, Daniel Bur, Lars Prade, Patrick Hess, Panja Strickner, Walter Fischli, Beat Steiner, Alexander Treiber

Affiliation

¹ Drug Discovery Chemistry & Biochemistry, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland.

PMID: 20843686
DOI: 10.1016/j.bmcl.2010.08.086

Abstract

The discovery of a new series of piperidine-based renin inhibitors is described herein. SAR optimization upon the P3 renin sub-pocket is described, leading to the discovery of 9 and 41, two bioavailable renin inhibitors orally active at low doses in a transgenic rat model of hypertension.

MeSH terms

Animals
Antihypertensive Agents / pharmacology
Blood Pressure / drug effects
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme Inhibitors
Drug Design
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology*
Models, Molecular
Piperidines / chemical synthesis*
Piperidines / chemistry
Piperidines / pharmacology*
Protein Conformation
Rats
Renin / antagonists & inhibitors*
Structure-Activity Relationship
X-Ray Diffraction

Substances

Antihypertensive Agents
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Piperidines
Cyp3a2 protein, rat
Cytochrome P-450 CYP3A
Renin