lp533401 and Osteoporosis--Postmenopausal

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