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 <b>5</b>, we discovered compound <b>11</b> (MT-7117: dersimelagon phosphoric acid). This compound exhibited strong MC1R agonistic activity, good pharmacokinetic properties, and excellent safety profiles. Furthermore, compound <b>11</b> was effective in animal pigmentation evaluation and skin fibrosis model studies. Compound <b>11</b> 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.