Discovery of a BBB-Penetrant Lanosterol Derivative as an Aβ Aggregation Inhibitor for Alzheimer's Disease.

The abnormal aggregation of amyloid-beta (Aβ) peptides is a core driver of Alzheimer's disease (AD). Developing central nervous system (CNS)-penetrant small-molecule Aβ inhibitors offers a complementary strategy to overcome the high costs and severe side effects of antibodies. Lanosterol has demonstrated excellent potential in inhibiting abnormal protein aggregation. However, poor physicochemical and pharmacokinetic profiles strictly hinder its direct therapeutic application. Herein, rational modifications on lanosterol were conducted to modulate the hydrophilic-lipophilic balance around the 3-hydroxyl group and aliphatic side chain. This systematic screening led to compound 10, a highly active candidate with significantly improved metabolic stability and physicochemical properties. Furthermore, oral administration of 10 rescued cognitive memory deficits and reduced the Aβ burden in the AD mouse model. This work provides a promising, CNS-active candidate for AD intervention, demonstrating that rational structural optimization of bioactive substances is a valuable strategy in the discovery of novel therapeutics for CNS diseases.