Discovery of a Potent and Orally Bioavailable Melatonin Receptor Agonist

To develop potent and orally bioavailable melatonin receptor (MT₁ and MT₂) agonists, a novel series of 5–6–5 tricyclic derivatives was designed, synthesized, and evaluated. The synthesized indeno­[5,4-d]­[1,3]­oxazole, cyclopenta­[c]­pyrazolo­[1,5-a]­pyridine, indeno­[5,4-d]­[1,3]­thiazole, and cyclopenta­[e]­indazole derivatives showed potent binding affinities for MT₁/MT₂ receptors. Further optimization of these derivatives based on their metabolic stability in human hepatic microsomes revealed that (S)-3b ((S)-N-[2-(2-methyl-7,8-dihydro-6H-indeno­[5,4-d]­[1,3]­oxazol-8-yl)­ethyl]­acetamide) was a potent MT₁ and MT₂ ligand (MT₁, K_i = 0.031 nM; MT₂, K_i = 0.070 nM) with good metabolic stability in human hepatic microsomes. Moreover, compound (S)-3b showed good BBB permeability in rats, and its in vivo pharmacological effects were confirmed by its sleep-promotion ability in cats.