Research, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Takeda California Inc., 9625 Towne Centre Drive, San Diego, California 92121, United States.
J Med Chem. 2022 Feb 24;65(4):3343-3358. doi: 10.1021/acs.jmedchem.1c01898. Epub 2022 Feb 15.
Cholesterol 24-hydroxylase (CH24H or CYP46A1) is a brain-specific cytochrome P450 enzyme that metabolizes cholesterol into 24-hydroxycholesterol (24HC) for regulating brain cholesterol homeostasis. For the development of a novel and potent CH24H inhibitor, we designed and synthesized 3,4-disubstituted pyridine derivatives using a structure-based drug design approach starting from compounds (soticlestat) and (thioperamide). Optimization of this series by focusing on ligand-lipophilicity efficiency value resulted in the discovery of 4-(4-methyl-1-pyrazolyl)pyridine derivative (IC = 8.5 nM) as a potent and highly selective CH24H inhibitor. The X-ray crystal structure of CH24H in complex with compound revealed a unique binding mode. Both blood-brain barrier penetration and reduction of 24HC levels (26% reduction) in the mouse brain were confirmed by oral administration of at 30 mg/kg, indicating that is a promising tool for the novel and selective inhibition of CH24H.
胆固醇 24-羟化酶（CH24H 或 CYP46A1）是一种脑特异性细胞色素 P450 酶，可将胆固醇代谢为 24-羟胆固醇（24HC），以调节脑内胆固醇稳态。为了开发新型强效 CH24H 抑制剂，我们采用基于结构的药物设计方法，从化合物 （soticlestat）和 （thioperamide）出发，设计并合成了 3,4-二取代吡啶衍生物。通过关注配体脂溶性效率值对该系列化合物进行优化，发现了 4-（4-甲基-1-吡唑基）吡啶衍生物 （IC = 8.5 nM），它是一种强效且高度选择性的 CH24H 抑制剂。CH24H 与化合物 形成复合物的 X 射线晶体结构揭示了一种独特的结合模式。化合物 在 30 mg/kg 剂量下经口服给药，可确认其具有良好的血脑屏障穿透性，并能降低小鼠脑中的 24HC 水平（降低 26%），表明 是一种有前途的新型和选择性 CH24H 抑制剂工具。
