Identification of New Non-BBB Permeable Tryptophan Hydroxylase Inhibitors for Treating Obesity and Fatty Liver Disease.
Suvarna H PagireHaushabhau S PagireKun-Young ParkEun Jung BaeKwang-Eun KimMinhee KimJihyeon YoonSaravanan ParameswaranJun-Ho ChoiSungmi ParkJae-Han JeonJin Sook SongMyung Ae BaeIn-Kyu LeeHail KimJae Myoung SuhJin Hee AhnPublished in: Molecules (Basel, Switzerland) (2022)
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 IC 50 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.
Keyphrases
- weight gain
- weight loss
- blood brain barrier
- body mass index
- birth weight
- insulin resistance
- metabolic syndrome
- high fat diet induced
- type diabetes
- fatty acid
- adipose tissue
- chemotherapy induced
- gene expression
- cerebrospinal fluid
- photodynamic therapy
- bioinformatics analysis
- skeletal muscle
- drug delivery
- drug release
- preterm birth