Ursolic acid derivatives as bone anabolic agents targeted to tryptophan hydroxylase 1 (Tph-1)

Tryptophan hydroxylase 1 (Tph-1) initiates the biosynthesis of peripheral serotonin. As peripheral serotonin suppresses bone formation, inhibitor of Tph-1 provides a useful tool to discover anabolic agents for osteoporosis. In the present study, series of ursolic acid (UA) derivatives were synthesized, and their inhibitory activity on serotonin biosynthesis and cytotoxicity were evaluated. Among the derivatives, 8d with potent inhibitory activity on serotonin was applied for further research. The data revealed that 8d significantly inhibited protein and mRNA expressions of Tph-1, and an SPR study indicated that 8d directly interacted to Tph-1 with a binding affinity of KD = 15.09 μM. Oral administration of 8d significantly prevented bone loss via suppressing serotonin biosynthesis without estrogenic side-effects in ovariectomized (OVX) rats.

Graphical abstractSeries of ursolic acid derivatives were synthesized, and their inhibitory activity on serotonin was screened. Compound 8d suppressed Tph-1 and prevented bone loss in an anabolic fashion.Download high-res image (178KB)Download full-size image