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) Ligan

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• 作者：Tatsuki Koike ; Takafumi Takai ; Yasutaka Hoashi ; Masaharu Nakayama ; Yohei Kosugi ; Masato Nakashima ; Shin-ichi Yoshikubo ; Keisuke Hirai ; Osamu Uchikawa
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：June 23, 2011
• 年：2011
• 卷：54
• 期：12
• 页码：4207-4218
• 全文大小：1030K
• 年卷期：v.54,no.12(June 23, 2011)
• ISSN：1520-4804

文摘

Novel tricyclic dihydrofuran derivatives were designed, synthesized, and evaluated as melatonin receptor (MT₁/MT₂) 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 MT₁/MT₂ agonist 4d (MT₁, K_i = 0.062 nM; MT₂, K_i = 0.420 nM) with good oral absorption and blood鈥揵rain 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.