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].
体内研究
When administered orally daily for up to 6 weeks, LP-533401 dose-dependently prevents and reverses osteoporosis in ovariectomized rodents by selectively increasing bone formation, without significant absorption into the brain, as indicated by its negligible brain levels and inability to cross the blood-brain barrier in pharmacokinetic studies[1].
Repeated treatment with LP-533401 results in significant reductions in 5-HT content in the gut, lungs, and blood of mice, without affecting brain 5-HT levels, which underscores its effect on serotonin synthesis outside the central nervous system[2].
In healthy adult mice, treatment with LP-533401 leads to a 30% decrease in circulating serotonin levels and a consequent 30% increase in osteoblast numbers. Furthermore, in mice injected with EL4 cells, LP-533401 treatment inhibits reductions in osteoblast numbers and trabecular bone volume, prolongs survival, and diminishes leukemic infiltration, showcasing its potential in bone health and leukemia intervention[3].
体外研究
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].
作用机制
LP-533401 interacts with two amino acids, Tyr235 and Phe241, near Tph1 catalytic site. [2]
LP-533401 细胞实验
Cell Line
Concentration
Treated Time
Description
References
RIN-14B cells
2 μM
48 hours
Inhibition of Tph1 function, alleviating hypoxia-induced oxidative stress
Int J Mol Sci. 2019 Mar 18;20(6):1364
LP-533401 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
High-fat diet-induced hepatic steatosis model
Oral gavage
30 mg/kg
Once daily for 12 weeks
To evaluate the effect of LP-533401 on high-fat diet-induced hepatic steatosis. Results showed that LP-533401 reduced HFD-induced hepatic triglyceride accumulation.
Diabetes Metab J. 2018 Jun;42(3):233-243
Sprague-Dawley rats
High fat-sucrose diet-induced non-alcoholic steatohepatitis (NASH) model
Gavage
17.5 mg/kg/day
Once daily for 20 or 30 days
To evaluate the effect of LP533401 on the progression of NASH. Results showed that LP533401 treatment significantly reduced 5-HT levels in serum and duodenum, and decreased hepatic lipid accumulation and inflammatory response.
Front Pharmacol. 2020 May 14;11:553
Rats
Chronic kidney disease model
Oral gavage
30 and 100 mg/kg
Once daily for eight weeks
To investigate the effect of LP533401 on bone mineral status in rats with chronic kidney disease, finding that LP533401 treatment improved bone mineral status by modulating the kynurenic system in bone.
Int J Mol Sci. 2020 Aug 19;21(17):5979
Rats (Rattus norvegicus albinus, Wistar)
Ligature-induced periodontal disease model
Gavage
25 mg/kg/d
Once daily for 28 days
To evaluate the effects of LP533401 in a rat periodontitis model on alveolar bone destruction and area of collagen. Results showed that LP533401 (25 mg/kg/d) for 28 d does not prevent bone loss and does not modulate host response in a rat model of induced periodontal disease.
J Periodontal Res. 2016 Oct;51(5):661-8
Mice
Hyperlipidemic mouse model induced by atherogenic diet
Infusion
25 mg/kg bw
16 weeks (young mice) or 8 weeks (older mice)
To evaluate the effects of LP533401 on skeletal bone mineral density (BMD) and aortic calcification in hyperlipidemic mice. Results showed that LP533401 blunted skeletal bone loss in lumbar vertebrae and the initial development of aortic calcification in young mice, but only increased lumbar BMD in older mice with limited effects on the progression of aortic calcification.
Biochem Biophys Res Commun. 2024 May 28;710:149854
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