Preparation, Antiepileptic Activity, and Cardiovascular Safety of Dihydropyrazoles as Brain-Penetrant T-Type Calcium Channel Blockers

J Med Chem. 2016 Sep 22;59(18):8398-411. doi: 10.1021/acs.jmedchem.6b00756.

Lubos Remen ¹, Olivier Bezençon ¹, Lloyd Simons ², Rick Gaston ², Dennis Downing ², John Gatfield ¹, Catherine Roch ¹, Melanie Kessler ¹, Johannes Mosbacher ¹, Thomas Pfeifer ¹, Corinna Grisostomi ¹, Markus Rey ¹, Eric A Ertel ¹, Richard Moon ¹

Affiliations

1 Drug Discovery Chemistry, Biology and Pharmacology, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
2 Kalexsyn, Inc. , 4502 Campus Drive, Kalamazoo, Michigan 49008, United States.

PMID: 27579577 DOI: 10.1021/acs.jmedchem.6b00756

Abstract

A series of dihydropyrazole derivatives was developed as potent, selective, and brain-penetrating T-type calcium channel blockers. An optimized derivative, compound 6c, was advanced to in vivo studies, where it demonstrated efficacy in the WAG/Rij rat model of generalized nonconvulsive, absence-like epilepsy. Compound 6c was not efficacious in the basolateral amygdala kindling rat model of temporal lobe epilepsy, and it led to prolongation of the PR interval in ECG recordings in rodents.

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