Publication Details (including relevant citation information):
Richardson, Timothy I., Ornstein, Paul L., Briner, Karin, Fisher, Matthew J., Backer, Ryan T., Biggers, C. Kelly, Clay, Michael P., Emmerson, Paul J., Hertel, Larry W., Hsiung, Hansen M., Husain, Saba, Kahl, Steven D., Lee, Jonathan A., Lindstrom, Terry D., Martinelli, Michael J., Mayer, John P., Mullaney, Jeffery T., O'Brien, Thomas P., Pawlak, Joseph M., Revell, Kevin D., Shah, Jikesh, Zgombick, John M., Herr, R. Jason, Melekhov, Alex, Sampson, Peter B., King, Chi-Hsin R. Journal of Medicinal Chemistry 2004 47 (3) 744-755
Abstract: The melanocortin receptors have been implicated as potential targets for a number of important therapeutic indications, including inflammation, sexual dysfunction, and obesity. We identified compound 1, an arylpiperazine attached to the dipeptide H-D-Tic-D-p-Cl-Phe-OH, as a novel melanocortin subtype-4 receptor (MC4R) agonist through iterative directed screening of nonpeptidyl G-protein-coupled receptor biased libraries. Structure-activity relationship (SAR) studies demonstrated that substitutions at the ortho position of the aryl ring improved binding and functional potency. For example, the o-isopropyl-substituted compound 29 (Ki = 720 nM) possessed 9-fold better binding affinity compared to the unsubstituted aryl ring (Ki = 6600 nM). Sulfonamide 39 (Ki = 220 nM) fills this space with a polar substituent, resulting in a further 2-fold improvement in binding affinity. The most potent compounds such as the diethylamine 44 (Ki = 60 nM) contain a basic group at this position. Basic heterocycles such as the imidazole 50 (Ki = 110 nM) were similarly effective. We also demonstrated good oral bioavailability for sulfonamide 39.