Discovery and evaluation of Cav3.2-selective T-type calcium channel blockers

Olivier Bezençon; Luboš Remeň; Sylvia Richard; Catherine Roch; Melanie Kessler; Eric A Ertel; Richard Moon; Jacques Mawet; Thomas Pfeifer; Bruno Capeleto

doi:10.1016/j.bmcl.2017.09.062

Discovery and evaluation of Ca_v3.2-selective T-type calcium channel blockers

Bioorg Med Chem Lett. 2017 Dec 1;27(23):5326-5331. doi: 10.1016/j.bmcl.2017.09.062. Epub 2017 Sep 30.

Authors

Affiliations

¹ Drug Discovery Chemistry, Biology and Pharmacology, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland. Electronic address: olivier.bezencon@idorsia.com.
² Drug Discovery Chemistry, Biology and Pharmacology, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland.

PMID: 29074257
DOI: 10.1016/j.bmcl.2017.09.062

Abstract

We identified and characterized a series of pyrrole amides as potent, selective Ca_v3.2-blockers. This series culminated with the identification of pyrrole amides 13b and 26d, with excellent potencies and/or selectivities toward the Ca_v3.1- and Ca_v3.3-channels. These compounds display poor physicochemical and DMPK properties, making their use difficult for in vivo applications. Nevertheless, they are well-suited for in vitro studies.

Keywords: Absence-type epilepsy; Pyrroles; Selective Cav3.2-blockers; T-type calcium channel.

MeSH terms

Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Animals
Calcium Channel Blockers / chemical synthesis
Calcium Channel Blockers / chemistry
Calcium Channel Blockers / pharmacology*
Calcium Channels, T-Type / metabolism*
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Molecular Structure
Pyrroles / chemical synthesis
Pyrroles / chemistry
Pyrroles / pharmacology*
Rats
Structure-Activity Relationship

Substances

Amides
Calcium Channel Blockers
Calcium Channels, T-Type
Pyrroles