Structure-Activity Relationship Study on Soticlestat Derivatives for the Discovery of CYP46A1 (CH24H) Inhibitors.

ABSTRACT: Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare, severe developmental and epileptic encephalopathies with poor prognosis, and novel drugs are urgently needed to meet clinical needs. CYP46A1 (cholesterol 24-hydroxylase, CH24H) is mainly responsible for the metabolism of cholesterol to 24(S)-hydroxycholesterol in the brain and is implicated in many brain disorders through the mediation of excitatory amino acid transporter 2 (EAAT2) and N-methyl-D-aspartate (NMDA) receptors. Inhibition of CYP46A1 is supposed to provide a novel treatment for disorders associated with neural hyperexcitation, such as epilepsy and epileptic syndromes. Soticlestat, a potent CYP46A1 inhibitor being developed by Takeda, is indicated for LGS and DS but suffers from unsatisfactory in vivo potency in an

SUBMITTER: Hu X 

PROVIDER: S-EPMC12899276 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature