End-capping of the modified melanocortin tetrapeptide (p-Cl)Phe-D-Phe-Arg-Trp-NH2 as a route to hMC4R agonists

Of the 42 R′-X-(p-Cl)Phe-D-Phe-Arg-Trp-NH2 (X = CO, SO2, PO, PS) tested at the human (h)MC1, hMC3, and hMC4 receptors (R), the most potent MC4R agonists (EC50 of 8–20 nM) were obtained by end-capping with R′ = CH2 CHCH2 (9), NCCH2 (16), NH2COCH2 (17), HCONHCH2 (18), CH3NH (19), CH2 CHCH2NH (21), 2-Th (23), PhCH2 (30) and X = CO. These compounds possess 35–60-fold hMC4 versus hMC1Rs selectivity with urea LK-71 (19) being the most potent at hMC4R and MC4/1R selective (EC50 = 8.5 nM, MC4/1R = 100). LK-75 (16) combines high potency at hMC4R and MC4/3R selectivity (EC50 = 10.5 nM, MC4/3R = 290). SAR is discussed.