1610959-07-3Relevant academic research and scientific papers
Tryptophan hydroxylase 1 (Tph-1)-targeted bone anabolic agents for osteoporosis
Fu, Hai-Jian,Zhou, Yu-Ren,Bao, Bei-Hua,Jia, Meng-Xuan,Zhao, Yang,Zhang, Lei,Li, Jian-Xin,He, Hai-Lang,Zhou, Xian-Mei
, p. 4692 - 4709 (2014/07/07)
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.
