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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Published inJournal of medicinal chemistry Vol. 60; no. 23; pp. 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 Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 14.12.2017
Amer Chemical Soc
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
Chemistry, Medicinal
Dogs
Drug Discovery
Epilepsy, Generalized - drug therapy
Epilepsy, Generalized - metabolism
Guinea Pigs
Humans
Life Sciences & Biomedicine
Macaca fascicularis
Pharmacology & Pharmacy
Pyrazoles - chemistry
Pyrazoles - pharmacology
Rats, Wistar
Science & Technology
Structure-Activity Relationship
ABSENCE SEIZURES
QSAR MODELS
AMINES
PHARMACOLOGICAL CHARACTERIZATION
THERAPEUTIC TARGET
VALIDATION
INHIBITORS
AMES TEST
MIBEFRADIL RO 40-5967
MUTAGENICITY
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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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b01236