Discovery and characterization of a novel tryptophan hydroxylase 1 inhibitor as a prodrug

Shi, Hailong; Cui, Yaya; Qin, Yifei

doi:10.1111/cbdd.13071

Cited by 13 publications

(4 citation statements)

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“…Additionally, higher 5-HT content, higher TPH1 expression, and lower SERT mRNA were detected in both children and adults with IBS, compared with that of the controls ( Faure et al, 2010 ; Yu et al, 2016 ; Fu R. et al, 2019 ). Furthermore, TPH1 inhibition and colonic 5-HT content was significantly reduced, and visceral hyperalgesia was alleviated ( Shi et al, 2018 ). Together, these results indicate that ELS-induced CRH elevation and ECs increase.…”

Section: Links Between Enterochromaffin Cells Corticotropin-releasing...mentioning

confidence: 99%

Potential Roles of Enterochromaffin Cells in Early Life Stress-Induced Irritable Bowel Syndrome

Tao

Zhu

et al. 2022

Front. Cell. Neurosci.

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Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, also known as disorders of the gut–brain interaction; however, the pathophysiology of IBS remains unclear. Early life stress (ELS) is one of the most common risk factors for IBS development. However, the molecular mechanisms by which ELS induces IBS remain unclear. Enterochromaffin cells (ECs), as a prime source of peripheral serotonin (5-HT), play a pivotal role in intestinal motility, secretion, proinflammatory and anti-inflammatory effects, and visceral sensation. ECs can sense various stimuli and microbiota metabolites such as short-chain fatty acids (SCFAs) and secondary bile acids. ECs can sense the luminal environment and transmit signals to the brain via exogenous vagal and spinal nerve afferents. Increasing evidence suggests that an ECs-5-HT signaling imbalance plays a crucial role in the pathogenesis of ELS-induced IBS. A recent study using a maternal separation (MS) animal model mimicking ELS showed that MS induced expansion of intestinal stem cells and their differentiation toward secretory lineages, including ECs, leading to ECs hyperplasia, increased 5-HT production, and visceral hyperalgesia. This suggests that ELS-induced IBS may be associated with increased ECs-5-HT signaling. Furthermore, ECs are closely related to corticotropin-releasing hormone, mast cells, neuron growth factor, bile acids, and SCFAs, all of which contribute to the pathogenesis of IBS. Collectively, ECs may play a role in the pathogenesis of ELS-induced IBS. Therefore, this review summarizes the physiological function of ECs and focuses on their potential role in the pathogenesis of IBS based on clinical and pre-clinical evidence.

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Section: Links Between Enterochromaffin Cells Corticotropin-releasing...mentioning

confidence: 99%

Potential Roles of Enterochromaffin Cells in Early Life Stress-Induced Irritable Bowel Syndrome

Tao

Zhu

et al. 2022

Front. Cell. Neurosci.

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“…LX-1032 inhibits both TPH1 and TPH2 in vitro but selectively lowers 5-HT levels in the GI tract [33]. Most TPH inhibitors have similar affinity for TPH1 and TPH2; however, the pro-drug mol002291, derived from the Chinese herb Rheum officinalis, was recently described by Shi et al [34] as a TPH1 inhibitor showing selectivity over TPH2. Finally, a team at Novartis (Basel, Switzerland) recently reported a novel series of allosteric TPH1 inhibitors [35].…”

mentioning

confidence: 99%

Discovery and Biological Characterization of a Novel Scaffold for Potent Inhibitors of Peripheral Serotonin Synthesis

et al. 2020

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Aim: Tryptophan hydroxylase 1 (TPH1) catalyzes serotonin synthesis in peripheral tissues. Selective TPH1 inhibitors may be useful for treating disorders related to serotonin dysregulation. Results & methodology: Screening using a thermal shift assay for TPH1 binders yielded Compound 1 (2-(4-methylphenyl)-1,2-benzisothiazol-3(2 H)-one), which showed high potency (50% inhibition at 98 ± 30 nM) and selectivity for inhibiting TPH over related aromatic amino acid hydroxylases in enzyme activity assays. Structure–activity relationships studies revealed several analogs of 1 showing comparable potency. Kinetic studies suggested a noncompetitive mode of action of 1, with regards to tryptophan and tetrahydrobiopterin. Computational docking studies and live cell assays were also performed. Conclusion: This TPH1 inhibitor scaffold may be useful for developing new therapeutics for treating elevated peripheral serotonin.

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“…A recent publication claimed to have discovered a selective inhibitor of TPH-1, mol002291, a molecule derived from the Chinese herb Rheum officinale . This agent specifically inhibited in vitro TPH-1, reduced colonic 5-HT content and attenuated visceral hyperalgesia in rat models [ 79 ]. Further studies should analyze the effects of mol002291 on the development of CHD in BON-1 xenograft models [ 76 ].…”

Section: Future Therapies For Carcinoid Syndromementioning

confidence: 99%

Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies

Mantovani

Carra

Alessi³

et al. 2023

IJMS

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Carcinoid syndrome represents a debilitating paraneoplastic disease, caused by the secretion of several substances, occurring in about 10–40% of patients with well-differentiated neuroendocrine tumors (NETs). The main signs and symptoms associated with carcinoid syndrome are flushing, diarrhea, hypotension, tachycardia, bronchoconstriction, venous telangiectasia, dyspnea and fibrotic complications (mesenteric and retroperitoneal fibrosis, and carcinoid heart disease). Although there are several drugs available for the treatment of carcinoid syndrome, the lack of therapeutic response, poor tolerance or resistance to drugs are often reported. Preclinical models are indispensable tools for investigating the pathogenesis, mechanisms for tumor progression and new therapeutic approaches for cancer. This paper provides a state-of-the-art overview of in vitro and in vivo models in NETs with carcinoid syndrome, highlighting the future developments and therapeutic approaches in this field.

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Discovery and characterization of a novel tryptophan hydroxylase 1 inhibitor as a prodrug

Cited by 13 publications

References 50 publications

Potential Roles of Enterochromaffin Cells in Early Life Stress-Induced Irritable Bowel Syndrome

Potential Roles of Enterochromaffin Cells in Early Life Stress-Induced Irritable Bowel Syndrome

Discovery and Biological Characterization of a Novel Scaffold for Potent Inhibitors of Peripheral Serotonin Synthesis

Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies

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