色氨酸羟化酶催化血清素生物合成的第一步和限速步骤，血清素是一种众所周知的神经递质，在多种生理功能中发挥着重要作用。血清素水平降低，尤其是大脑中的血清素水平降低，可能会导致失调，导致抑郁或失眠。相反，外周血清素的过量产生与类癌综合征和肺动脉高压等症状有关。最近，我们开发了一类基于黄嘌呤-苯并咪唑的 TPH 抑制剂，其特征是跨越共底物蝶呤和底物色氨酸的结合位点的三方结合模式以及催化铁离子的螯合。在此，我们描述了第二代黄嘌呤-咪唑并吡啶和-咪唑并噻唑的基于结构的开发，旨在抑制外周的TPH1，同时防止与大脑中的TPH2相互作用。先导化合物 32 (TPT-004) 在外周血清素衰减和结直肠肿瘤生长的临床前模型中显示出优异的药代动力学和药效学特性以及功效。

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.