brain-penetrant CH24H inhibitor
Ph. 2 for epilepsies (up to 300 mg PO QD)
from SBDD
Journal of Medicinal Chemistry
Takeda, Fujisawa, Japan
The Takeda cholesterol 24-hydroxylase inhibitor, soticlestat (TAK-935, previously OV935) is a potent, highly selective, first-in-class inhibitor of the brain-specific enzyme cholesterol 24-hydroxylase (CH24H). Cholesterol 24-hydroxylase converts cholesterol to 24S-hydroxycholesterol, which acts as a positive allosteric modulator of N-methyl-D-aspartate (NMDA) receptors. Soticlestat blocks 24S-hydroxycholesterol production in the brain in an in vivo mouse model in a dose-dependent manner (1, 3, and 10 mg/kg). It is in Ph. III as a novel anti-epileptic, for pediatric epilepsies such as in Dravet syndrome and Lennox-Gastaut syndrome. The compound (IC50 = 7.4 nM) came from 4-arylpyridine derivatives identified in a high-throughput screening (HTS) campaign with further optimization utilizing structure based drug design (SBDD).