Goldilocks-Inspired Design of Mid-Size Macrocycles for Selective Targeting of Human Melanocortin Receptors.

The recent clinical success of macrocyclic peptides, such as bremelanotide and setmelanotide, highlights the potential of this modality as a "Goldilocks" chemical class, effectively balancing the properties of small molecules and biologics while optimizing their affinity, stability, and pharmacokinetics. Despite their potential, achieving selective MCR targeting with optimal pharmacological profiles remains challenging. Motivated by these considerations, we designed and synthesized a series of 14 macrocyclic peptide analogs (19-23-membered rings) based on MT-II, SHU-9119, and PG-901 scaffolds. Their pharmacological activities were assessed using human MC1R, MC3R, MC4R, and MC5R. The novel macrocyclic compounds FM648 and FM636 emerged as potent and selective hMC4R antagonists. Additionally, FM635 exhibited interesting agonist activity with remarkable selectivity for the same receptor. This study underscores the potential of tailored midsized macrocycles as selective MCR ligands and provides new insights into the structure-activity relationships, thereby guiding the development of therapeutic candidates for metabolic and inflammatory diseases.