Piperazinebenzylamines as potent and selective antagonists of the human melanocortin-4 receptor

Abstract

SAR studies of a series of piperazinebenzylamines resulted in the discovery of potent antagonists of the human melanocortin-4 receptor. Compounds 11c, 11d, and 11l, which had K i values of 21, 14, and 15 nM, respectively, possessed low efficacy in cAMP stimulation (∼15% of α-MSH maximal level) mediated by MC4R, and functioned as antagonists in inhibition of α-MSH-stimulated cAMP release in a dose-dependent manner (11l, IC 50 = 36 nM). © 2004 Elsevier Ltd. All rights reserved.