Discovery of spirocyclic proline tryptophan hydroxylase-1 inhibitors
| Autor: | Patricia Bourassa, Nicole Barucci, Stéphane De Lombaert, William J. Zavadoski, Daniel R. Goldberg, Qing Zhang, Robert J. Aiello, James J. Valentine, Vishwas M. Paralkar |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Serotonin Proline Clinical Biochemistry Pharmaceutical Science Tryptophan Hydroxylase Inhibitory postsynaptic potential Biochemistry Inhibitory Concentration 50 Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Drug Discovery Animals Humans Spiro Compounds Neurotransmitter Molecular Biology chemistry.chemical_classification Binding Sites TPH1 Aryl Organic Chemistry Brain Protein Structure Tertiary Rats Amino acid Molecular Docking Simulation 030104 developmental biology Monoamine neurotransmitter chemistry Drug Design Molecular Medicine Half-Life Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 26:1124-1129 |
| ISSN: | 0960-894X |
| Popis: | The central role of the biogenic monoamine serotonin (5-hydroxytryptamine, 5-HT) as a neurotransmitter with important cognitive and behavioral functions is well known. However, 5-HT produced in the brain only accounts for approximately 5% of the total amount of 5-HT generated in the body. At the onset of our work, it appeared that substituted phenylalanine derivatives or related aryl amino acids were required to produce potent inhibitors of TPH1, as significant losses of inhibitory activity were noted in the absence of this structural element. We disclose herein the discovery of a new class of TPH1 inhibitors that significantly lower peripherally 5-HT. |
| Databáze: | OpenAIRE |
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