Structure-activity relationships of piperazinebenzylamines as potent and selective agonists of the human melanocortin-4 receptor

Bioorg Med Chem Lett. 2004 Sep 6;14(17):4417-23. doi: 10.1016/j.bmcl.2004.06.059.

Joseph Pontillo ¹, Joseph A Tran, Melissa Arellano, Beth A Fleck, Rajesh Huntley, Dragan Marinkovic, Marion Lanier, Jodie Nelson, Jessica Parker, John Saunders, Fabio C Tucci, Wanlong Jiang, Caroline W Chen, Nicole S White, Alan C Foster, Chen Chen

Affiliations

Affiliation

1 Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, USA.

PMID: 15357964 DOI: 10.1016/j.bmcl.2004.06.059

Abstract

SAR studies on a series of piperazinebenzenes directed toward the human melanocortin-4 receptor resulted in potent MC4R agonists. Replacement of the triazole moiety of an initial lead 4 by a basic nitrogen baring a lipophilic side-chain increased the binding affinities of these compounds. Analogs bearing an additional hetero-atom in the side-chain possessed good agonist potency. Thus, 11h had a Ki of 11 nM, and 13g exhibited an EC50 of 3.8 nM and a Ki of 6.4 nM.

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