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Discovery of a Potent and Orally Bioavailable Melatonin Receptor Agonist

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journal contribution
posted on 08.03.2021, 06:14 by Yasutaka Hoashi, Takafumi Takai, Yohei Kosugi, Masato Nakashima, Masaharu Nakayama, Keisuke Hirai, Osamu Uchikawa, Tatsuki Koike
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, Ki = 0.031 nM; MT2, Ki = 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.