Discovery of 4-Phenylpiperidine-2-Carboxamide Analogues as Serotonin 5-HT2C Receptor-Positive Allosteric Modulators with Enhanced Drug-like Properties
| Autor: | Christopher Wild, Joanna Miszkiel, Robert G. Fox, Jianping Chen, Eric A. Wold, Kathryn A. Cunningham, Noelle C. Anastasio, Erik J. Garcia, Konrad Pazdrak, Claudia A. Soto, Jia Zhou |
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| Rok vydání: | 2020 |
| Předmět: |
Agonist
medicine.drug_class Allosteric regulation Carboxamide CHO Cells Pharmacology 01 natural sciences Article Structure-Activity Relationship 03 medical and health sciences Cricetulus Piperidines In vivo Drug Discovery Receptor Serotonin 5-HT2C medicine Animals Receptor 030304 developmental biology 0303 health sciences Binding Sites Molecular Structure Chemistry 0104 chemical sciences Molecular Docking Simulation 5-HT2C receptor 010404 medicinal & biomolecular chemistry Drug Design Lipophilicity Molecular Medicine Serotonin Serotonin 5-HT2 Receptor Agonists |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.9b01953 |
| Popis: | Targeting the serotonin (5-HT) 5-HT(2C) receptor (5-HT(2C)R) allosteric site to potentiate endogenous 5-HT tone may provide novel therapeutics to alleviate the impact of costly, chronic diseases such as obesity and substance use disorders. Expanding upon our recently described 5-HT(2C)R-positive allosteric modulators (PAMs) based on the 4-alkylpiperidine-2-carboxamide scaffold, we optimized the undecyl moiety at the 4-position with variations of cyclohexyl- or phenyl-containing fragments to reduce rotatable bonds and lipophilicity. Compound 12 (CTW0415) was discovered as a 5-HT(2C)R PAM with improved pharmacokinetics and reduced off-target interactions relative to our previous series of molecules. The in vivo efficacy of compound 12 to potentiate the effects of a selective 5-HT(2C)R agonist was established in a drug discrimination assay. Thus, 12 is reported as a 5-HT(2C)R PAM with characteristics suitable for in vivo pharmacological studies to further probe the biological and behavioral mechanisms of allosteric modulation of a receptor important in several chronic diseases. |
| Databáze: | OpenAIRE |
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