Structure-Based Design of Xanthine-Benzimidazole Derivatives as Novel and Potent Tryptophan Hydroxylase Inhibitors

Tryptophan hydroxylases catalyze the first and rate-limiting
step
in the synthesis of serotonin. Serotonin is a key neurotransmitter
in the central nervous system and, in the periphery, functions as
a local hormone with multiple physiological functions. Studies in
genetically altered mouse models have shown that dysregulation of
peripheral serotonin levels leads to metabolic, inflammatory, and
fibrotic diseases. Overproduction of serotonin by tumor cells causes
severe symptoms typical for the carcinoid syndrome, and tryptophan
hydroxylase inhibitors are already in clinical use for patients suffering
from this disease. Here, we describe a novel class of potent tryptophan
hydroxylase inhibitors, characterized by spanning all active binding
sites important for catalysis, specifically those of the cosubstrate
pterin, the substrate tryptophan as well as directly chelating the
catalytic iron ion. The inhibitors were designed to efficiently reduce
serotonin in the periphery while not passing the blood–brain
barrier, thus preserving serotonin levels in the brain.

色氨酸羟化酶（Tryptophan hydroxylases）催化5-羟色胺（serotonin）合成的第一步且为限速步骤。5-羟色胺是中枢神经系统中的关键神经递质，在外周组织中则作为兼具多种生理功能的局部激素发挥作用。基于基因工程改造小鼠模型的研究表明，外周5-羟色胺水平失调会引发代谢性、炎症性及纤维化疾病。肿瘤细胞过度合成5-羟色胺会引发类癌综合征（carcinoid syndrome）的典型重症症状，而色氨酸羟化酶抑制剂已被临床用于治疗该类疾病患者。本文报道一类新型强效色氨酸羟化酶抑制剂，其特征为可覆盖催化过程所需的全部关键活性结合位点，具体包括辅底物蝶呤、底物色氨酸的结合位点，还可直接螯合催化铁离子。该类抑制剂被设计为可高效降低外周5-羟色胺水平，同时无法透过血脑屏障（blood–brain barrier），因此能够维持脑部的5-羟色胺水平。