Peripheral Selective Oxadiazolylphenyl Alanine Derivatives as Tryptophan Hydroxylase 1 Inhibitors for Obesity and Fatty Liver Disease

Tryptophan hydroxylase 1 (TPH1) has
been recently suggested as
a promising therapeutic target for treating obesity and fatty liver
disease. A new series of 1,2,4-oxadiazolylphenyl alanine derivatives
were identified as TPH1 inhibitors. Among them, compound 23a was the most active in vitro, with an IC50 (half-maximal
inhibitory concentration) value of 42 nM, showed good liver microsomal
stability, and showed no significant inhibition of CYP and hERG. Compound 23a inhibited TPH1 in the peripheral tissue with limited BBB
penetration. In high-fat diet-fed mice, 23a reduced body
weight gain, body fat, and hepatic lipid accumulation. Also, 23a improved glucose intolerance and energy expenditure. Taken
together, compound 23a shows promise as a therapeutic
agent for the treatment of obesity and fatty liver diseases.