Melanocortin-1 receptor (MC1R) is primarily activated by α-melanocyte-stimulating hormone (α-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 α-MSH analog MC1R agonist, is clinically 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.

黑皮质素 1 受体 (MC1R) 主要由 α-促黑素细胞激素 (α-MSH) 激活，并发挥着至关重要的作用，例如保持皮肤稳态以抵抗黑素生成和外部刺激、抗炎作用和组织纤维化抑制. Afamelanotide 是一种 α-MSH 类似物 MC1R 激动剂，临床上用于通过皮下植入给药治疗红细胞原卟啉症 (EPP)。因此，我们发起了一项针对口服可用的小分子非肽 MC1R 激动剂的调查。从内部命中化合物6a进行优化，最终发现了带有异哌啶酸基团的 N-(1-苄基-1H-咪唑-2-基) 酰胺衍生物9g，其具有良好的 MC1R 激动活性和代谢稳定性。