lp533401 and Osteoporosis

The molecular elucidation of two human skeletal dysplasias revealed that they are caused by an increase or a decrease in the synthesis of serotonin by enterochromaffin cells of the gut. This observation revealed a novel and powerful endocrine means to regulate bone mass. Exploiting these findings in the pharmacological arena led to the demonstration that inhibiting synthesis of gut-derived serotonin could be an effective means to treat low-bone-mass diseases such as osteoporosis.

Topics: Animals; Bone Density; Clinical Trials as Topic; Duodenum; Female; Humans; LDL-Receptor Related Proteins; Low Density Lipoprotein Receptor-Related Protein-5; Mice; Osteogenesis Imperfecta; Osteoporosis; Pyrimidines; Rats; Serotonin; Serotonin Antagonists; Tryptophan Hydroxylase

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.

Topics: Anabolic Agents; Animals; Bone and Bones; Brain; Cell Line; Female; Gastrointestinal Tract; Humans; Molecular Docking Simulation; Osteoporosis; Ovariectomy; Protein Binding; Quinoxalines; Rats; RNA, Messenger; Serotonin; Structure-Activity Relationship; Surface Plasmon Resonance; Triterpenes; Tryptophan Hydroxylase; Ursolic Acid

In a proof-of-concept study it was shown that decreasing synthesis of gut serotonin through a small molecule inhibitor of Tph1 could prevent and treat ovariectomy-induced osteoporosis in young mice and rats. In this study, we define the minimal efficacy of this Tph1 inhibitor, demonstrate that its activity is improved with the duration of treatment, and show that its anabolic effect persists on interruption. Importantly, given the prevalence of osteoporosis in the aging population, we then show that Tph1 inhibition rescues ovariectomy-induced bone loss in aged mice. It also cures the low bone mass of Lrp5-deficient mice through a sole anabolic effect. Lastly, we provide evidence that inhibition of gut serotonin synthesis can work in concert with an antiresorptive agent to increase bone mass in ovariectomized mice. This study provides a more comprehensive view of the anabolic efficacy of Tph1 inhibitors and further establishes the spectrum of their therapeutic potential in the treatment of bone-loss disorders.

Topics: Aging; Alendronate; Animals; Bone and Bones; Bone Resorption; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Gastrointestinal Tract; Low Density Lipoprotein Receptor-Related Protein-5; Mice; Mice, Inbred C57BL; Organ Size; Osteoporosis; Ovariectomy; Phenotype; Pyrimidines; Serotonin; Time Factors; Treatment Outcome; Tryptophan Hydroxylase

Osteoporosis is a disease of low bone mass most often caused by an increase in bone resorption that is not sufficiently compensated for by a corresponding increase in bone formation. As gut-derived serotonin (GDS) inhibits bone formation, we asked whether hampering its biosynthesis could treat osteoporosis through an anabolic mechanism (that is, by increasing bone formation). We synthesized and used LP533401, a small molecule inhibitor of tryptophan hydroxylase-1 (Tph-1), the initial enzyme in GDS biosynthesis. Oral administration of this small molecule once daily for up to six weeks acts prophylactically or therapeutically, in a dose-dependent manner, to treat osteoporosis in ovariectomized rodents because of an isolated increase in bone formation. These results provide a proof of principle that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis.

Topics: Animals; Dose-Response Relationship, Drug; Female; Gastrointestinal Tract; Humans; Mice; Mice, Inbred C57BL; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Pyrimidines; Rats; Serotonin; Serotonin Agents; Tryptophan Hydroxylase