Design, optimization, and in vivo evaluation of a series of pyridine derivatives with dual NK1 antagonism and SERT inhibition for the treatment of depression
| Autor: | Yu-Wen Li, George O. Tora, Snjezana Lelas, Kim A. Johnson, Matthew T. Taber, Joanne J. Bronson, Michael F. Parker, Rudolf G. Krause, Amy Newton, Robert L. Bertekap, Kelly D. Lengyel, Kevin W. Gillman, Nicholas J. Lodge, Rick L. Pieschl, John E. Macor, Andrew P. Degnan, Silva Mark, Sarah J. Taylor |
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| Rok vydání: | 2013 |
| Předmět: |
Phenylpiperidine
Pyridines Stereochemistry Clinical Biochemistry Pharmaceutical Science Ether Pharmacology Gerbil Biochemistry Inhibitory Concentration 50 chemistry.chemical_compound Neurokinin-1 Receptor Antagonists In vivo Drug Discovery Pyridine Animals Receptor Molecular Biology Molecular Structure Depression Chemistry Organic Chemistry Disease Models Animal Drug Design Molecular Medicine Serotonin Antagonists Gerbillinae Antagonism Behavioural despair test |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 23:407-411 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2012.11.094 |
| Popis: | A series of substituted pyridines, ether linked to a phenylpiperidine core were optimized for dual NK(1)/SERT affinity. Optimization based on NK(1)/SERT binding affinities, and minimization of off-target ion channel activity lead to the discovery of compound 44. In vivo evaluation of 44 in the gerbil forced swim test (a depression model), and ex-vivo NK(1)/SERT receptor occupancy data support the potential of a dual acting compound for the treatment of depression. |
| Databáze: | OpenAIRE |
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