Discovery of MT-7117 (Dersimelagon Phosphoric Acid): A Novel, Potent, Selective, and Nonpeptidic Orally Available Melanocortin 1 Receptor Agonist

Activation of the melanocortin 1 receptor (MC1R) mediates melanogenesis in melanocytes, anti-inflammatory effects in inflammatory cells, and antifibrotic effects in fibroblasts. Thus, MC1R agonists are expected to be beneficial for treating skin, autoimmune, inflammatory, and fibrotic diseases. Afamelanotide, an α-melanocyte-stimulating hormone (α-MSH) analogue MC1R agonist, is used clinically for treating erythropoietic protoporphyria (EPP) as a subcutaneous implant formulation. We explored nonpeptidic small-molecule MC1R agonists with the aim of identifying more convenient oral drugs. By exploring the structure of previously reported compound 5, we discovered compound 11 (MT-7117: dersimelagon phosphoric acid). This compound exhibited strong MC1R agonistic activity, good pharmacokinetic properties, and excellent safety profiles. Furthermore, compound 11 was effective in animal pigmentation evaluation and skin fibrosis model studies. Compound 11 is currently in clinical trials for the treatment of EPP, X-linked protoporphyria (XLP), and systemic sclerosis (SSc). Proof of concept was obtained in phase 2 clinical studies on EPP and XLP.