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

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 <b>6c</b>, was advanced to in vivo studies, where it demonstrated efficacy in the WAG/Rij rat model of generalized nonconvulsive, absence-like epilepsy. Compound <b>6c</b> 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

Discovery of a Potent, Selective T‑type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies

We report here the discovery and pharmacological characterization of <i>N</i>-(1-benzyl-1<i>H</i>-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound <b>66b</b> (ACT-709478), which has been selected as a clinical candidate