Discovery of a Potent and Orally Bioavailable Melatonin Receptor Agonist

To develop potent and orally bioavailable melatonin receptor (MT 1 and MT 2 ) 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 MT 1 /MT 2 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-6 H -indeno[5,4- d ][1,3]oxazol-8-yl)ethyl]acetamide) was a potent MT 1 and MT 2 ligand (MT 1 , K i = 0.031 nM; MT 2 , 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.