Discovery of 1-{2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-4-methyl-phenyl}-4-[(2R)-methyl-3-(4-chlorophenyl)-propionyl]piperazine as an orally active antagonist of the melanocortin-4 receptor for the potential treatment of cachexia

A potent and Selective antagonist of the melanocortin-4 receptor, 1-{2-[(IS)-(3-dimethylaminopropionyl)amino-2-methylpropyl}-6-methylphenyl}-4-[(2R)-methyl-3-(4-chlorophenyl)propionyl]pip- erazine (10d), was identified from a series piperazinebenzylamine attached with a N,N-dimethyl-beta-alanine side chain. This compound possessed high water solubility and exhibited good metabolic profiles. In animals, 10d showed moderate to good oral bioavailability and promoted food intake in tumor-bearing mice after oral administration.