Discovery of MT-7117\n(Dersimelagon Phosphoric Acid):\nA Novel, Potent, Selective, and Nonpeptidic Orally Available Melanocortin\n1 Receptor Agonist

Activation\nof the melanocortin 1 receptor (MC1R) mediates melanogenesis\nin melanocytes, anti-inflammatory effects in inflammatory cells, and\nantifibrotic effects in fibroblasts. Thus, MC1R agonists are expected\nto be beneficial for treating skin, autoimmune, inflammatory, and\nfibrotic diseases. Afamelanotide, an α-melanocyte-stimulating\nhormone (α-MSH) analogue MC1R agonist, is used clinically for\ntreating erythropoietic protoporphyria (EPP) as a subcutaneous implant\nformulation. We explored nonpeptidic small-molecule MC1R agonists\nwith the aim of identifying more convenient oral drugs. By exploring\nthe structure of previously reported compound <b>5</b>, we discovered\ncompound <b>11</b> (MT-7117: dersimelagon phosphoric acid).\nThis compound exhibited strong MC1R agonistic activity, good pharmacokinetic\nproperties, and excellent safety profiles. Furthermore, compound <b>11</b> was effective in animal pigmentation evaluation and skin\nfibrosis model studies. Compound <b>11</b> is currently in clinical\ntrials for the treatment of EPP, X-linked protoporphyria (XLP), and\nsystemic sclerosis (SSc). Proof of concept was obtained in phase 2\nclinical studies on EPP and XLP.