Identification of Tryptophan Hydroxylase 1(TPH1) inhibitors for metabolic disease

Abstract

Serotonin, which is a well-known neurotransmitter that regulates feeling in the central nervous system(CNS), has been emerging as a target for the treatment of metabolic diseases since it is also involved in the energy accumulation process in the periphery. Meanwhile, serotonin in CNS and periphery have therapeutically opposite direction. Since serotonin can’t penetrate across the blood-brain barrier (BBB), we can selectively suppress the biosynthesis of the peripheral serotonin through the inhibition of TPH1. In this thesis, xanthine derivatives are synthesized and evaluated for their TPH inhibition. Among them, compound 40a which has phenacyl moiety shows a good in vitro activity against TPH1 and liver microsomal stability with non-BBB permeability.