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

## TL;DR

This study explores chemical modifications of soticlestat to improve its effectiveness as a CYP46A1 inhibitor for treating severe epilepsies like Dravet and Lennox–Gastaut syndromes.

## Contribution

The study identifies new soticlestat derivatives with potent CYP46A1 inhibition and reveals insights into their structure–activity relationships.

## Key findings

- Three soticlestat derivatives with benzenesulfonamide showed potent CYP46A1 inhibition comparable to soticlestat.
- A flat SAR profile was observed in some subseries, indicating structural flexibility for inhibition.
- The findings offer valuable guidance for designing novel CYP46A1 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 animal models and clinical trials. We designed three series of soticlestat derivatives to explore the structure–activity relationship (SAR) with the aim of finding more potent CYP46A1 inhibitors and understanding the SAR of CYP46A1 inhibitors represented by soticlestat. Eventually, three compounds with a benzenesulfonamide moiety (in subseries C-4) that serves as an isostere of OH in soticlestat were discovered with very potent CYP46A1 inhibitory activities comparable to soticlestat, and an interesting flat SAR profile was observed in some subseries. The findings in the present study provide insight into the SAR of CYP46A1 inhibitors and should be valuable for the future design of novel CYP46A1 inhibitors.