Synthesis and characterization of trans-4-(4-chlorophenyl)pyrrolidine-3-carboxamides of piperazinecyclohexanes as ligands for the melanocortin-4 receptor

Caroline W Chen; Joe A Tran; Beth A Fleck; Fabio C Tucci; Wanlong Jiang; Chen Chen

doi:10.1016/j.bmcl.2007.10.032

Synthesis and characterization of trans-4-(4-chlorophenyl)pyrrolidine-3-carboxamides of piperazinecyclohexanes as ligands for the melanocortin-4 receptor

Bioorg Med Chem Lett. 2007 Dec 15;17(24):6825-31. doi: 10.1016/j.bmcl.2007.10.032. Epub 2007 Oct 17.

Authors

Caroline W Chen¹, Joe A Tran, Beth A Fleck, Fabio C Tucci, Wanlong Jiang, Chen Chen

Affiliation

¹ Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA.

PMID: 17964151
DOI: 10.1016/j.bmcl.2007.10.032

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 18 v was found to bind MC4R with potent affinity (K(i)=0.5 nM) and high selectivity over the other melanocortin subtypes and behaved as a functional antagonist (IC(50)=48 nM).

MeSH terms

Amides / chemistry*
Carboxylic Acids / chemistry*
Chlorine Compounds / chemical synthesis*
Chlorine Compounds / chemistry
Cyclohexanes / chemistry*
Cyclohexanes / pharmacology
Ligands
Molecular Structure
Piperazine
Piperazines / chemistry*
Pyrrolidines / chemistry*
Receptor, Melanocortin, Type 4 / agonists
Receptor, Melanocortin, Type 4 / metabolism*
Structure-Activity Relationship

Substances

Amides
Carboxylic Acids
Chlorine Compounds
Cyclohexanes
Ligands
Piperazines
Pyrrolidines
Receptor, Melanocortin, Type 4
Piperazine
pyrrolidine