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 N-(1-benzyl-1H-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 66b (ACT-709478),
which has been selected as a clinical candidate.