title: Synthesis of a novel series of tricyclic dihydrofuran derivatives: discovery of 8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridines as melatonin receptor (MT1/MT2) ligands.
abstract: Novel tricyclic dihydrofuran derivatives were designed, synthesized, and evaluated as melatonin receptor (MT(1)/MT(2)) ligands based on the previously reported 1,6-dihydro-2H-indeno[5,4-b]furan 1a. By screening the central tricyclic cores, we identified 8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridine as a potent scaffold with a high ligand-lipophilicity efficiency (LLE) value. Subsequent optimization of the side chains led to identification of the potent MT(1)/MT(2) agonist 4d (MT(1), K(i) = 0.062 nM; MT(2), K(i) = 0.420 nM) with good oral absorption and blood-brain barrier (BBB) penetration in rats. The oral administration of compound 4d exhibited a sleep-promoting action in freely moving cats at 0.1 mg/kg.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85 Jusohonmachi, 2-Chome, Yodogawa-ku, Osaka 532-8686, Japan. Koike_Tatsuki@takeda.co.jp
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Koike
authors.forename: Takafumi
authors.initials: T
authors.lastname: Takai
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Hoashi
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nakayama
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kosugi
authors.forename: Masato
authors.initials: M
authors.lastname: Nakashima
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Yoshikubo
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hirai
authors.forename: Osamu
authors.initials: O
authors.lastname: Uchikawa
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism; D016466:CHO Cells; D002415:Cats; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D005260:Female; D005663:Furans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D044122:Receptor, Melatonin, MT1 / Q000378:metabolism*; D044123:Receptor, Melatonin, MT2 / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D005663:Furans; D006575:Heterocyclic Compounds, 3-Ring; D008024:Ligands; C561057:N-(2-(2-ethyl-8,9-dihydrofuro(3,2-c)pyrazolo(1,5-a)pyridin-1-yl)ethyl)acetamide; D011720:Pyrazoles; D011725:Pyridines; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D000242:Cyclic AMP