jm0c01836_si_001.pdf (458.67 kB)
Download fileDiscovery of a Potent and Orally Bioavailable Melatonin Receptor Agonist
journal contribution
posted on 2021-03-08, 06:14 authored by Yasutaka Hoashi, Takafumi Takai, Yohei Kosugi, Masato Nakashima, Masaharu Nakayama, Keisuke Hirai, Osamu Uchikawa, Tatsuki KoikeTo 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.