Discovery of acyl guanidine tryptophan hydroxylase-1 inhibitors
| Autor: | Nicole Barucci, Stéphane De Lombaert, Vishwas M. Paralkar, Jim Valentine, William J. Zavadoski, Patricia Bourassa, Robert J. Aiello, A.J. Stein, Daniel R. Goldberg, Qing Zhang |
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| Rok vydání: | 2016 |
| Předmět: |
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Molecular 0301 basic medicine Stereochemistry Clinical Biochemistry Pharmaceutical Science Tryptophan Hydroxylase Biochemistry Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Biosynthesis Drug Discovery Humans Structure–activity relationship Enzyme Inhibitors Guanidine Molecular Biology 5-HT receptor TPH1 Dose-Response Relationship Drug Molecular Structure Organic Chemistry Tryptophan hydroxylase Oxidoreductase inhibitor 030104 developmental biology chemistry 030220 oncology & carcinogenesis Molecular Medicine Serotonin |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 26:2855-2860 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2016.04.057 |
| Popis: | An increasing number of diseases have been linked to a dysfunctional peripheral serotonin system. Given that tryptophan hydroxylase 1 (TPH1) is the rate limiting enzyme in the biosynthesis off serotonin, it represents an attractive target to regulate peripheral serotonin. Following up to our first disclosure, we report a new chemotype of TPH1 inhibitors where-by the more common central planar heterocycle has been replaced with an open-chain, acyl guanidine surrogate. Through our work, we found that compounds of this nature provide highly potent TPH1 inhibitors with favorable physicochemical properties that were effective in reducing murine intestinal 5-HT in vivo. Furthermore, we obtained a high resolution (1.90Å) X-ray structure crystal structure of one of these inhibitors (compound 51) that elucidated the active conformation along with revealing a dimeric form of TPH1 for the first time. |
| Databáze: | OpenAIRE |
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