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
  • 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.