Discovery of novel bridged tetrahydronaphthalene derivatives as potent T/L-type calcium channel blockers

Dorte Renneberg; Francis Hubler; Markus Rey; Patrick Hess; Stephane Delahaye; John Gatfield; Marc Iglarz; Kurt Hilpert

doi:10.1016/j.bmcl.2015.07.038

Discovery of novel bridged tetrahydronaphthalene derivatives as potent T/L-type calcium channel blockers

Bioorg Med Chem Lett. 2015 Sep 15;25(18):3941-6. doi: 10.1016/j.bmcl.2015.07.038. Epub 2015 Jul 21.

Authors

Dorte Renneberg¹, Francis Hubler², Markus Rey², Patrick Hess², Stephane Delahaye², John Gatfield², Marc Iglarz², Kurt Hilpert²

Affiliations

¹ Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. Electronic address: dorte.renneberg@actelion.com.
² Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.

PMID: 26231163
DOI: 10.1016/j.bmcl.2015.07.038

Abstract

Chemical evolution of mibefradil resulted in the identification of novel bridged tetrahydronaphthalene derivatives as potent T/L-type calcium channel blockers. A SAR study, in vitro and in vivo DMPK properties as well as the in vivo antihypertensive effect in rats are presented.

Keywords: Antihypertensive effect; Bridged tetrahydronaphthalene; Calcium channel blocker; Mibefradil; T/L-type calcium channels.

MeSH terms

Animals
Calcium Channel Blockers / chemical synthesis
Calcium Channel Blockers / chemistry*
Calcium Channel Blockers / pharmacology*
Calcium Channels / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Molecular Conformation
Rats
Rats, Inbred SHR
Structure-Activity Relationship
Tetrahydronaphthalenes / chemical synthesis
Tetrahydronaphthalenes / chemistry*
Tetrahydronaphthalenes / pharmacology*

Substances

Calcium Channel Blockers
Calcium Channels
Tetrahydronaphthalenes