Journal of Medicinal Chemistry
Journal of Medicinal Chemistry
5 years ago

Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies

Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies
Bruno Capeleto, Bibia Heidmann, Eric A. Ertel, Romain Siegrist, Richard Moon, Michael Toeroek-Schafroth, Elvire Fournier, Davide Pozzi, Jacques Mawet, Markus Rey, Sylvia Richard, Olivier Bezençon, Ruben de Kanter, Simon Stamm, Isabelle Reymond, Melanie Kessler, Olivier Corminboeuf, Luca G. Moccia, Catherine Roch, Thomas Pfeifer
We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b01236

DOI: 10.1021/acs.jmedchem.7b01236

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