ArticleACS pharmacology & translational science2025
Selectivity and Safety Characterization of a Xanthine-Imidazothiazole Lead Structure: a Novel Tryptophan Hydroxylase Inhibitor of Peripheral Serotonin Synthesis.
Article in ACS pharmacology & translational science, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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8 authors.
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Abstract
Serotonin (5-HT), a crucial neurotransmitter and peripheral mediator, regulates various physiological processes and is synthesized by tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme responsible for its production. 5-HT overproduction is implicated in multiple diseases, making TPH1 a promising therapeutic target. However, selectivity remains a challenge due to the structural similarity of TPH1 with other members of the aromatic amino acid hydroxylase (AAAH) family, including TPH2, phenylalanine hydroxylase (PAH), and tyrosine hydroxylase (TH). This study aimed to evaluate the selectivity and inhibitory potential of TPT-004, a novel TPH inhibitor, compared with Telotristat (LP778902) and its prodrug (LX1606). We developed high-throughput fluorescence assays to evaluate the inhibitory effects of the test compounds on TPH1, TPH2, PAH, and TH enzymes. TPT-004 demonstrated high selectivity for TPHs compared to LP778902 and LX1606. Structural analysis based on a detailed sequence alignment within the AAAH enzyme family, combined with cocrystal structures of TPH1 and TPH2 bound to different generations of inhibitors, enhances our understanding of the molecular basis of inhibitor binding and provides a framework for explaining TPT-004's selectivity for TPHs. Selectivity profiling against 97 targets confirmed that TPT-004 showed minimal off-target interactions, underscoring its specificity. A dose-range finding (DRF) study in rats assessed the
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