CHI3L1-IN-5

Z17 (CAS No.: 2249043-42-1) is a highly specific CHI3L1 inhibitor obtained through structure-activity relationship optimization based on the lead compound E14 (CAS No.: 2224165-92-6). It binds specifically to CHI3L1 in a 1:1 mode (KD=6.0 μM) and possesses excellent central nervous system penetration potential (LogD7.4=2.39, PAMPA permeability=4.6×10⁻⁶ cm/s) as well as favorable pharmacokinetic properties (human plasma half-life=3.4±0.3 h, hERG inhibition IC50>100 μM). By blocking the CHI3L1-mediated NF-κB inflammatory pathway and dose-dependently restoring Aβ uptake and lysosomal function in astrocytes, Z17 exerts dual effects of anti-inflammation and cellular function repair. Its specificity is significantly superior to that of the reference compound G28, providing a novel candidate drug with both druggability and a clear mechanism for Alzheimer's disease, as well as a new paradigm for the targeted treatment of neuroinflammation-related neurodegenerative diseases.

References:

[1] Nada H, Zhang L, Kaur B, Vázquez NG, Gabr M. Restoring Amyloid Clearance via Astrocytes: Z17 Is a Selective Inhibitor of CHI3L1 in Alzheimers Disease. bioRxiv [Preprint]. 2025 Dec 10:2025.12.07.692801. doi: 10.64898/2025.12.07.692801. PMID: 41415431; PMCID: PMC12709476.