LP-533401 is a Tryptophan hydroxylase 1 inhibitor that regulates serotonin production in the gut.
LP-533401 completely inhibits serotonin production in Tph1–expressing cells (RBL2H3 cells) at a dose of 1 μM[1].
Oral administration once daily for up to 6 weeks of this small molecule prevents the development of and fully rescues, in a dose-dependent manner, osteoporosis in ovariectomized rodents because of an isolated increase in bone formation. Pharmacokinetic studies in rodents show that LP-533401 level in the brain is negligible following oral administration, indicating that it is virtually unable to cross the blood-brain barrier[1]. Mice treated repeatedly with LP-533401 (30–250 mg/kg per day) exhibit marked 5-HT content reductions in the gut, lungs, and blood, but not in the brain. After a single LP533401 dose (250 mg/kg), lung and gut 5-HT contents decrease by 50%, whereas blood 5-HT levels remain unchanged, suggesting gut and lung 5-HT synthesis[2]. Adult, healthy mice treated with the Tph-1 inhibitor LP-533401 show 30% decrease in circulating serotonin levels, with a consequent 30% increase in osteoblast numbers. Administration of LP533401 to mice injected with EL4 cells inhibits the decrement in osteoblast numbers and trabecular bone volume, prolongs survial, and decreases leukemic infiltration[3].
References:
[1]. Yadav, V.K., et al. Inhibition of gut-derived serotonin synthesis: A potential bone anabolic treatment. Nat. Med. 16(3), 308-312 (2010).
[2]. Abid S, et al. Inhibition of gut- and lung-derived serotonin attenuates pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol. 2012 Sep 15;303(6):L500-8.
[3]. Krevvata M, et al. Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts. Blood. 2014 Oct 30;124(18):2834-46.