Tryptophan hydroxylase 1 (Tph-1)-targeted bone anabolic agents for osteoporosis.


Tryptophan hydroxylase 1 (Tph-1), the principal enzyme for peripheral serotonin biosynthesis, provides a novel target to design anabolic agents for osteoporosis. Here, we present a design, synthesis of a novel series of ursolic acid derivatives under the guidance of docking technique, and bioevaluation of the derivatives using RBL2H3 cells and ovariectomized (OVX) rats. Of the compounds, 9a showed a potent inhibitory activity on serotonin biosynthesis. Further investigations revealed that 9a, as an efficient Tph-1 binder identified by SPR (estimated KD: 6.82 μM), suppressed the protein and mRNA expressions of Tph-1 and lowered serotonin contents in serum and gut without influence on brain serotonin. Moreover, oral administration of 9a elevated serum level of N-terminal propeptide of procollagen type 1 (P1NP), a bone formation marker, and improved bone microarchitecture without estrogenic side effects in ovariectomized rats. Collectively, 9a may serve as a new candidate for bone anabolic drug discovery.

DOI: 10.1021/jm5002293

Cite this paper

@article{Fu2014TryptophanH1, title={Tryptophan hydroxylase 1 (Tph-1)-targeted bone anabolic agents for osteoporosis.}, author={Hai-Jian Fu and Yu-ren Zhou and Bei-hua Bao and Meng-Xuan Jia and Yang Zhao and Lei Zhang and Jian-Xin Li and Hai-Lang He and Xianmei Zhou}, journal={Journal of medicinal chemistry}, year={2014}, volume={57 11}, pages={4692-709} }