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.
State Key Lab of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University , 22 Hankou Road, Nanjing 210093, P. R. China.
Hai-Jian
HJ
Fu
Yu-Ren
YR
Zhou
Bei-Hua
BH
Bao
Meng-Xuan
MX
Jia
Yang
Y
Zhao
Lei
L
Zhang
Jian-Xin
JX
Li
Hai-Lang
HL
He
Xian-Mei
XM
Zhou
D045930:Anabolic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D010024:Osteoporosis / Q000188:drug therapy* / Q000378:metabolism; D010052:Ovariectomy; D011485:Protein Binding; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012701:Serotonin / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism*; D000097245:Ursolic Acid
D045930:Anabolic Agents; D011810:Quinoxalines; D012333:RNA, Messenger; D012701:Serotonin; D014315:Triterpenes; D014365:Tryptophan Hydroxylase; D000097245:Ursolic Acid; C497467:TPH1 protein, human; C494784:TPH2 protein, human