2 research outputs found
Structure–Activity Relationship, Drug Metabolism and Pharmacokinetics Properties Optimization, and <i>in Vivo</i> Studies of New Brain Penetrant Triple T‑Type Calcium Channel Blockers
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 <b>4</b>, optimization
work led to the preparation of pyridodiazepine <b>31c</b> with
improved physicochemical properties, solubility, and metabolic stability.
The racemic mixture was separated by chiral preparative HPLC, and
the resulting lead compound <b>(3</b><i><b>R</b></i><b>,5</b><i><b>S</b></i><b>)-31c</b> showed
promising efficacy in the WAG/Rij-rat model of generalized nonconvulsive
absence-like epilepsy
Structure–Activity Relationship, Drug Metabolism and Pharmacokinetics Properties Optimization, and <i>in Vivo</i> Studies of New Brain Penetrant Triple T‑Type Calcium Channel Blockers
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 <b>4</b>, optimization
work led to the preparation of pyridodiazepine <b>31c</b> with
improved physicochemical properties, solubility, and metabolic stability.
The racemic mixture was separated by chiral preparative HPLC, and
the resulting lead compound <b>(3</b><i><b>R</b></i><b>,5</b><i><b>S</b></i><b>)-31c</b> showed
promising efficacy in the WAG/Rij-rat model of generalized nonconvulsive
absence-like epilepsy