Identification of New Non-BBB Permeable Tryptophan Hydroxylase Inhibitors for Treating Obesity and Fatty Liver Disease

Author:

Pagire Suvarna H.ORCID,Pagire Haushabhau S.ORCID,Park Kun-YoungORCID,Bae Eun JungORCID,Kim Kwang-eunORCID,Kim Minhee,Yoon JihyeonORCID,Parameswaran SaravananORCID,Choi Jun-Ho,Park Sungmi,Jeon Jae-Han,Song Jin Sook,Bae Myung Ae,Lee In-Kyu,Kim Hail,Suh Jae Myoung,Ahn Jin HeeORCID

Abstract

Serotonin (5-hydroxytryptophan) is a hormone that regulates emotions in the central nervous system. However, serotonin in the peripheral system is associated with obesity and fatty liver disease. Because serotonin cannot cross the blood-brain barrier (BBB), we focused on identifying new tryptophan hydroxylase type I (TPH1) inhibitors that act only in peripheral tissues for treating obesity and fatty liver disease without affecting the central nervous system. Structural optimization inspired by para-chlorophenylalanine (pCPA) resulted in the identification of a series of oxyphenylalanine and heterocyclic phenylalanine derivatives as TPH1 inhibitors. Among these compounds, compound 18i with an IC50 value of 37 nM was the most active in vitro. Additionally, compound 18i showed good liver microsomal stability and did not significantly inhibit CYP and Herg. Furthermore, this TPH1 inhibitor was able to actively interact with the peripheral system without penetrating the BBB. Compound 18i and its prodrug reduced body weight gain in mammals and decreased in vivo fat accumulation.

Funder

National Research Foundation of Korea

Korea Institute of Energy Technology Evaluation and Planning

Publisher

MDPI AG

Subject

Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science

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