Journal of Medicinal Chemistry p. 10661 - 10675 (2016)
Update date:2022-08-15
Topics:
Siegrist, Romain
Pozzi, Davide
Jacob, Ga?l
Torrisi, Caterina
Colas, Kilian
Braibant, Bertrand
Mawet, Jacques
Pfeifer, Thomas
De Kanter, Ruben
Roch, Catherine
Kessler, Melanie
Corminboeuf, Olivier
Bezen?on, Olivier
Despite the availability of numerous antiepileptic drugs, 20-30% of epileptic patients are pharmacoresistant with seizures not appropriately controlled. Consequently, new strategies to address this unmet medical need are required. T-type calcium channels play a key role in neuronal excitability and burst firing, and selective triple T-type calcium channel blockers could offer a new way to treat various CNS disorders, in particular epilepsy. Herein we describe the identification of new 1,4-benzodiazepines as brain penetrant and selective triple T-type calcium channel blockers. From racemic hit 4, optimization work led to the preparation of pyridodiazepine 31c with improved physicochemical properties, solubility, and metabolic stability. The racemic mixture was separated by chiral preparative HPLC, and the resulting lead compound (3R,5S)-31c showed promising efficacy in the WAG/Rij-rat model of generalized nonconvulsive absence-like epilepsy.
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