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

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2016-09, Vol.59 (18), p.8398-8411
Main Authors: Remen, Lubos, Bezençon, Olivier, Simons, Lloyd, Gaston, Rick, Downing, Dennis, Gatfield, John, Roch, Catherine, Kessler, Melanie, Mosbacher, Johannes, Pfeifer, Thomas, Grisostomi, Corinna, Rey, Markus, Ertel, Eric A, Moon, Richard
Format: Article
Language:English
Subjects:
Animals
Anticonvulsants - chemistry
Anticonvulsants - pharmacokinetics
Anticonvulsants - therapeutic use
Brain - drug effects
Brain - metabolism
Brain - physiopathology
Calcium Channel Blockers - chemistry
Calcium Channel Blockers - pharmacokinetics
Calcium Channel Blockers - therapeutic use
Calcium Channels, T-Type - metabolism
Disease Models, Animal
Dogs
Electroencephalography
Epilepsy - drug therapy
Epilepsy - metabolism
Epilepsy - physiopathology
Humans
Kindling, Neurologic - drug effects
Male
Pyrazoles - chemistry
Pyrazoles - pharmacokinetics
Pyrazoles - therapeutic use
Rats, Wistar
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b00756