Cholesterol 24-hydroxylase (CH24H), also commonly known as CYP46A1, is a brain-specific enzyme. This enzyme is a member of the cytochrome P450 (CYP) superfamily of enzymes. Cholesterol 24-hydroxylase is a monooxygenase that hydroxylates the side-chain of cholesterol. And it converts cholesterol into 24S-hydroxycholesterol, which is the main mechanism of cholesterol catabolism in the brain. Therefore, it is responsible for the majority of cholesterol turnover in the human central nervous system. Moreover, cholesterol 24-hydroxylase has a variety of substrates, including: elongated steroid chains, cholesterol derivatives, and a variety of drug candidates. Furthermore, cholesterol 24-hydroxylase is a prime candidate for drug therapy for Alzheimer’s disease (AD) or other brain injuries.

Soticlestat (TAK-935; OV935) is a first-in-class, selective, high affinity, and orally active cholesterol 24-hydroxylase (CYP46A1) inhibitor. It inhibits the catalytic activity of human cholesterol 24-hydroxylase in a dose-dependent manner. However, Soticlestat does not inhibit the activity of other major CNS (central nervous system) drug targets and drug-metabolizing enzymes. Compared with the wild-type control, cholesterol 24-hydroxylase knockout mice showed a substantially lower level of Soticlestat distribution in the brain. Additionally, in a transgenic mouse model carrying human amyloid precursor protein and presenilin 1 (APP/PS1-Tg), Soticlestat lowers brain 24S-hydroxycholesterol in a dose-dependent manner. In addition, Soticlestat substantially reduced premature deaths of APP/PS1-Tg mice. Furthermore, Soticlestat can also inhibit the potassium-evoked extracellular glutamate elevations in the hippocampus.

Taken together, Soticlestat is a first-in-class and orally active cholesterol 24-hydroxylase inhibitor. Soticlestat-mediated cholesterol 24-hydroxylase inhibition may have therapeutic potential for diseases related to neural hyperexcitation. Moreover, Soticlestat has the potential for epilepsy syndromes research.


[1] Toshiya Nishi, et al. Sci Rep. 2020 Oct 13;10(1):17081.