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Discovery of a Potent and Orally Bioavailable Melatonin Receptor Agonist. 2021

Yasutaka Hoashi, and Takafumi Takai, and Yohei Kosugi, and Masato Nakashima, and Masaharu Nakayama, and Keisuke Hirai, and Osamu Uchikawa, and Tatsuki Koike
Takeda Pharmaceutical Company, Ltd.., 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.

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.

UI MeSH Term Description Entries
D007191 Indazoles A group of heterocyclic aromatic organic compounds consisting of the fusion of BENZENE and PYRAZOLES. Indazole
D008297 Male Males
D011725 Pyridines Compounds with a six membered aromatic ring containing NITROGEN. The saturated version is PIPERIDINES.
D001812 Blood-Brain Barrier Specialized non-fenestrated tightly-joined ENDOTHELIAL CELLS with TIGHT JUNCTIONS that form a transport barrier for certain substances between the cerebral capillaries and the BRAIN tissue. Brain-Blood Barrier,Hemato-Encephalic Barrier,Barrier, Blood-Brain,Barrier, Brain-Blood,Barrier, Hemato-Encephalic,Barriers, Blood-Brain,Barriers, Brain-Blood,Barriers, Hemato-Encephalic,Blood Brain Barrier,Blood-Brain Barriers,Brain Blood Barrier,Brain-Blood Barriers,Hemato Encephalic Barrier,Hemato-Encephalic Barriers
D003412 Cricetulus A genus of the family Muridae consisting of eleven species. C. migratorius, the grey or Armenian hamster, and C. griseus, the Chinese hamster, are the two species used in biomedical research. Hamsters, Armenian,Hamsters, Chinese,Hamsters, Grey,Armenian Hamster,Armenian Hamsters,Chinese Hamster,Chinese Hamsters,Grey Hamster,Grey Hamsters,Hamster, Armenian,Hamster, Chinese,Hamster, Grey
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013844 Thiazoles Heterocyclic compounds where the ring system is composed of three CARBON atoms, a SULFUR and NITROGEN atoms. Thiazole
D016466 CHO Cells CELL LINE derived from the ovary of the Chinese hamster, Cricetulus griseus (CRICETULUS). The species is a favorite for cytogenetic studies because of its small chromosome number. The cell line has provided model systems for the study of genetic alterations in cultured mammalian cells. CHO Cell,Cell, CHO,Cells, CHO
D017207 Rats, Sprague-Dawley A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company. Holtzman Rat,Rats, Holtzman,Sprague-Dawley Rat,Rats, Sprague Dawley,Holtzman Rats,Rat, Holtzman,Rat, Sprague-Dawley,Sprague Dawley Rat,Sprague Dawley Rats,Sprague-Dawley Rats

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