Tuned lanosterol derivative crosses the BBB and curbs Aβ burden in AD mice
- Lanosterol inhibits protein aggregation but has poor physicochemical and PK properties, so the authors tuned the hydrophilic–lipophilic balance around the 3-hydroxyl and the aliphatic side chain.
- Systematic screening gave compound 10, with markedly better metabolic stability and drug-like properties.
- Oral dosing of 10 rescued memory deficits and reduced Aβ burden in an Alzheimer's mouse model.
💡 Points
Natural-product sterols rarely survive their first PK table, so getting oral CNS exposure by tuning polarity around the 3-OH and side chain is the part I'd borrow. The open question is mechanism: efficacy in one mouse model is easy to over-read, and I'd want target engagement and sterol-pathway off-target data before getting excited.