Discovery of a Potent and Orally Bioavailable Melatonin Receptor Agonist.

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