Tryptophan Hydroxylase 1 (Tph-1)-Targeted Bone Anabolic Agents for Osteoporosis
详细信息 查看全文
- 作者：Hai-Jian Fu ; Yu-Ren Zhou ; Bei-Hua Bao ; Meng-Xuan Jia ; Yang Zhao ; Lei Zhang ; Jian-Xin Li ; Hai-Lang He ; Xian-Mei Zhou
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：June 12, 2014
- 年：2014
- 卷：57
- 期：11
- 页码：4692-4709
- 全文大小：641K
- 年卷期：v.57,no.11(June 12, 2014)
- ISSN：1520-4804
文摘
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 渭M), 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.