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