Structure-based design of a novel series of cholesterol 24-hydroxylase (CH24H) inhibitors bearing 1,3-oxazole as a heme-iron binding group.

Herein, we describe the design, synthesis, and pharmacological evaluation of novel 1,3-oxazole-based inhibitors of cholesterol 24-hydroxylase (CH24H; CYP46A1), a brain-specific cytochrome P450 (CYP) enzyme that metabolizes cholesterol to 24Shydroxycholesterol (24HC). Starting with compound 1a, a scaffold-hopping approach using structure-based drug design identified a series of imidazo[1,2-a]pyridine-3- carboxamide derivatives as novel CH24H inhibitors. Subsequent optimization guided by ligand-lipophilicity efficiency metrics resulted in the discovery of 3k (IC50 = 4.5 nM) with potent and selective CH24H inhibition. Oral administration of compound 3k at 10 mg/kg resulted in brain penetration and 24HC reduction in the mouse brain. These results suggest that 1,3-oxazole is a promising heme-iron binder which can provide potent and selective inhibitors against CYP enzymes, including CH24H.