A solid-phase approach to mouse melanocortin receptor agonists derived from a novel thioether cyclized peptidomimetic...

The solid-phase synthesis of a novel thioether cyclized peptidomimetic scaffold, displaying functionality at the i to i + 3 positions, is reported. The thioether bridge is formed on-bead by an intramolecular reaction between a chloroacetylated reduced peptide bond and the free thiol from a cysteine. The crude products were obtained in moderate to very high purity. A series of 19 compounds were prepared and tested for agonist activity at the mouse melanocortin receptors 1, 3, 4, and 5 (mMC1-5R). From these results, several compounds were identified as having low micromolar agonist activity at the mMC1R and mMC4R. The former is involved in skin pigmentation and animal coat coloration. The latter is involved in the regulation of appetite and food intake and is currently a drug target for potential treatment of obesity. The most potent compound 1n with the pharmacophore motif "His-DPhe-Arg-Trp" was identified as having an EC(50) value of 165 nM at mMC1R, 7600 nM at mMC3R, 650 nM at mMC4R, and 335 nM at mMC5R. In addition, some of the compounds showed moderate selectivity for the mMC1R.