Structure-based design of xanthine-imidazopyridines and -imidazothiazoles as highly potent and in vivo efficacious tryptophan hydroxylase inhibitors

Item Type:	Article
Title:	Structure-based design of xanthine-imidazopyridines and -imidazothiazoles as highly potent and in vivo efficacious tryptophan hydroxylase inhibitors
Creators Name:	Specker, E. and Wesolowski, R. and Schütz, A. and Matthes, S. and Mallow, K. and Wasinska-Kalwa, M. and Winkler, L. and Oder, A. and Alenina, N. and Pleimes, D. and von Kries, J.P. and Heinemann, U. and Bader, M. and Nazaré, M.
Abstract:	Tryptophan hydroxylases catalyze the first and rate-limiting step in the biosynthesis of serotonin, a well-known neurotransmitter that plays an important role in multiple physiological functions. A reduction of serotonin levels, especially in the brain, can cause dysregulation leading to depression or insomnia. In contrast, overproduction of peripheral serotonin is associated with symptoms like carcinoid syndrome and pulmonary arterial hypertension. Recently, we developed a class of TPH inhibitors based on xanthine-benzimidazoles, characterized by a tripartite-binding mode spanning the binding sites of the cosubstrate pterin and the substrate tryptophan and by chelation of the catalytic iron ion. Herein, we describe the structure-based development of a second generation of xanthine-imidiazopyridines and -imidazothiazoles designed to inhibit TPH1 in the periphery while preventing the interaction with TPH2 in the brain. Lead compound 32 (TPT-004) shows superior pharmacokinetic and pharmacodynamic properties as well as efficacy in preclinical models of peripheral serotonin attenuation and colorectal tumor growth.
Keywords:	Serotonin, Tryptophan Hydroxylase, Tryptophan, Xanthine
Source:	Journal of Medicinal Chemistry
ISSN:	0022-2623
Publisher:	American Chemical Society (ACS)
Volume:	66
Number:	21
Page Range:	14866-14896
Date:	9 November 2023
Official Publication:	https://doi.org/10.1021/acs.jmedchem.3c01454
PubMed:	View item in PubMed

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