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Synthesis and characterization of trans-4-(4-chlorophenyl)pyrrolidine-3-carboxamides of piperazinecyclohexanes as ligands for the melanocortin-4 receptor |
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| Authors: | Chen Caroline W Tran Joe A Fleck Beth A Tucci Fabio C Jiang Wanlong Chen Chen |
| Affiliation: | aDepartment of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA bDepartment of Pharmacology, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA |
| Abstract: | A series of trans-N-alkyl-4-(4-chlorophenyl)pyrrolidine-3-carboxamides of piperazinecyclohexanemethylamines was synthesized and characterized for binding and function at the melanocortin-4 receptor (MC4R), and several potent benzylamine derivatives were identified. Compound 18v was found to bind MC4R with potent affinity (Ki = 0.5 nM) and high selectivity over the other melanocortin subtypes and behaved as a functional antagonist (IC50 = 48 nM). |
| Keywords: | Synthesis Pyrrolidine Melanocortin-4 receptor Agonist Antagonist Structure–activity relationship |
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