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 I...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2021-01, Vol.64 (2), p.1037-1053
Main Authors: Bae, Eun Jung, Choi, Won Gun, Pagire, Haushabhau S, Pagire, Suvarna H, Parameswaran, Saravanan, Choi, Jun-Ho, Yoon, Jihyeon, Choi, Won-il, Lee, Ji Hun, Song, Jin Sook, Bae, Myung Ae, Kim, Mijin, Jeon, Jae-Han, Lee, In-Kyu, Kim, Hail, Ahn, Jin Hee
Format: Article
Language:English
Subjects:
Adiposity - drug effects
Alanine - analogs & derivatives
Alanine - chemical synthesis
Alanine - pharmacology
Animals
Anti-Obesity Agents - chemical synthesis
Anti-Obesity Agents - pharmacology
Anti-Obesity Agents - therapeutic use
Diet, High-Fat
Energy Metabolism - drug effects
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
Fatty Liver - drug therapy
Glucose Intolerance - drug therapy
Humans
Lipid Metabolism - drug effects
Liver - drug effects
Liver - metabolism
Mice
Mice, Inbred C57BL
Microsomes, Liver - metabolism
Models, Molecular
Tryptophan Hydroxylase - antagonists & inhibitors
Weight Gain - drug effects
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c01560