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

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 m...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2017-12, Vol.60 (23), p.9769-9789
Main Authors: Bezençon, Olivier, Heidmann, Bibia, Siegrist, Romain, Stamm, Simon, Richard, Sylvia, Pozzi, Davide, Corminboeuf, Olivier, Roch, Catherine, Kessler, Melanie, Ertel, Eric A., Reymond, Isabelle, Pfeifer, Thomas, de Kanter, Ruben, Toeroek-Schafroth, Michael, Moccia, Luca G., Mawet, Jacques, Moon, Richard, Rey, Markus, Capeleto, Bruno, Fournier, Elvire
Format: Article
Language:English
Subjects:
Animals
Benzeneacetamides - chemistry
Benzeneacetamides - metabolism
Benzeneacetamides - pharmacokinetics
Benzeneacetamides - pharmacology
Brain - drug effects
Brain - metabolism
Calcium Channel Blockers - chemistry
Calcium Channel Blockers - metabolism
Calcium Channel Blockers - pharmacokinetics
Calcium Channel Blockers - pharmacology
Calcium Channels, T-Type - metabolism
Dogs
Drug Discovery
Epilepsy, Generalized - drug therapy
Epilepsy, Generalized - metabolism
Guinea Pigs
Humans
Macaca fascicularis
Pyrazoles - chemistry
Pyrazoles - pharmacology
Rats, Wistar
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b01236