Paul Ornstein - Synthesis and structure-activity relationships of novel arylpiperazines as potent and selective agonists of the melanocortin subtype-4 receptor.

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  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.

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