Milestones to the Discovery of T-type Calcium Channel Blockers for the Treatment of Generalized Epilepsies
Keywords:Absence epilepsy, Ames test, Lead optimization, T-type calcium channel blockers
AbstractWe describe the discovery and optimization of new, brain-penetrant T-type calcium channel blockers. We present optimized compounds with excellent efficacy in a rodent model of generalized absence-like epilepsy. Along the fine optimization of a chemical series with a pharmacological target located in the CNS (target potency, brain penetration, and solubility), we successfully identified an Ames negative aminopyrazole as putative metabolite of this compound series. Our efforts culminated in the selection of compound 20, which was elected as a preclinical candidate.
How to Cite
O. Bezençon, T. Pfeifer, J. Mosbacher, I. Reymond, E. A. Ertel, R. de Kanter, B. Capeleto, E. Fournier, M. Rey, L. Moccia, M. Toeroek-Schafroth, R. Roscher, R. Moon, J. Gatfield, M. Kessler, R. Siegrist, B. Heidmann, D. Pozzi, S. Stamm, L. Remeň, S. Richard, L. Simons, R. Gaston, D. Downing, C. Grisostomi, C. Roch, B. Schindelholz, Chimia 2017, 71, 722, DOI: 10.2533/chimia.2017.722.
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