Discovery of novel N-(1-benzyl-1H-imidazol-2-yl)amide derivatives as melanocortin 1 receptor agonists

Melanocortin-1 receptor (MC1R) is primarily activated by alpha-melanocyte-stimulating hormone (alpha-MSH) and plays a crucial role, such as keeping homeostasis in the skin against melanogenesis and external stimuli, anti-inflammatory effects, and tissue fibrosis suppression. Afamelanotide, an alpha-MSH analog MC1R agonist, is clini-cally used for treating erythroblastic protoporphyria (EPP) by subcutaneous implantation administration. Therefore, we initiated an investigation aimed at orally available small molecule nonpeptide MC1R agonists. Optimization from the internal hit compound 6a finally resulted in the discovery of N-(1-benzyl-1H-imidazol-2-yl)amide derivative 9g bearing isonipecotinic acid moiety, which demonstrated good MC1R agonistic activity and metabolic stability.

Automated summary

Melanocortin-1 receptor (MC1R) is activated by alpha-melanocyte-stimulating hormone (alpha-MSH) and plays crucial roles in maintaining skin homeostasis, anti-inflammatory effects, and tissue fibrosis suppression. The discovery of N-(1-benzyl-1H-imidazol-2-yl)amide derivative 9g as a potent MC1R agonist with good metabolic stability is a significant advancement in the search for oral nonpeptide MC1R agonists.