Optimization of piperazinebenzylamines with a N-(1-methoxy-2-propyl) side chain as potent and selective antagonists of the human melanocortin-4 receptor

Piperazinebenzylamines bearing a small N-(1-methoxy-2-propyl) side chain were found to be potent and selective antagonists of the human melanocortin-4 (MC4) receptor. Compound 7b, having Ki values of 6.9 and 2800 nM at the human MC4 and MC3 receptors, respectively, has moderate oral bioavailability in mice, which is improved relative to the arylethyl analogues.