Abstract
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.
MeSH terms
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Animals
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Anticonvulsants / chemistry*
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Anticonvulsants / pharmacokinetics
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Anticonvulsants / therapeutic use*
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Brain / drug effects
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Brain / metabolism
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Brain / physiopathology
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Calcium Channel Blockers / chemistry*
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Calcium Channel Blockers / pharmacokinetics
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Calcium Channel Blockers / therapeutic use*
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Calcium Channels, T-Type / metabolism
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Disease Models, Animal
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Dogs
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Electroencephalography
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Epilepsy / drug therapy*
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Epilepsy / metabolism
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Epilepsy / physiopathology
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Humans
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Kindling, Neurologic / drug effects
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Male
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Pyrazoles / chemistry*
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Pyrazoles / pharmacokinetics
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Pyrazoles / therapeutic use*
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Rats, Wistar
Substances
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Anticonvulsants
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Calcium Channel Blockers
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Calcium Channels, T-Type
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Pyrazoles