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

著者: Lubos Remen†, Olivier Bezençon*†, Lloyd Simons‡, Rick Gaston‡, Dennis Downing‡, John Gatfield†, Catherine Roch†, Melanie Kessler†, Johannes Mosbacher†, Thomas Pfeifer†, Corinna Grisostomi†, Markus Rey†, Eric A. Ertel†, and Richard Moon†

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.