ACT-709478 is a potent, selective, orally-bioavailable and brain penetrant T-type calcium channel blocker with IC50 of 6.4, 18, and 7.5 nM for Cav3.1, Cav3.2, and Cav3.3 channels respectively.
T-type calcium channels (TTCCs) belong to the family of thelow-voltage-activated calcium channels. These channels are the products of three genes, CACNA1G, CACNA1H, and CACNA1I, yielding the Cav3.1, Cav3.2, and Cav3.3 channels, respectively. ACT-709478 blocked hCav3.3 potently but with marked voltage-dependency (Kr ≈ 1500 nM and Ki ≈ 20 nM). ACT-709478 blocked currents through hKv11.1-hERG channels with an IC50 of 5.5 μM. In WAG/Rij rats, 10 mg/kg po of ACT-709478 significantly decreased the cumulative duration of absence-like seizures over the next 12 h period by 93%, compared to a matched vehicle group. ACT-709478 completely suppressed the absence-type seizures over the first 6 h following administration. In the AGS model of juvenile DBA/2J mice, ACT-709478 showed a significant decrease of the seizure severity at a dose of 100 mg/kg po[1]. Ascending single oral doses of 1-400 mg ACT-709478 were administered to sequential groups of eight subjects. ACT-709478 exhibited good tolerability and safety after single-dose administration[2].
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