Synthesis, structure–activity relationships, and biological profiles of a dihydrobenzoxathiin class of histamine H₃ receptor inverse agonists

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• 作者：Takahide Sasaki ; Toshiyuki Takahashi ; Tsuyoshi Nagase ; Takashi Mizutani ; Sayaka Ito ; Yuko Mitobe ; Yasuhisa Miyamoto ; Maki Kanesaka ; Ryo Yoshimoto ; Takeshi Tanaka ; Norihiro Takenaga ; Shigeru Tokita ; Na
• 关键词：Histamine H₃ receptor inverse agonist ; CNS ; Dihydrobenzoxathiin derivative
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2009
• 出版时间：1 August 2009
• 年：2009
• 卷：19
• 期：15
• 页码：4232-4236
• 全文大小：981 K

文摘

A series of novel dihydrobenzoxathiin derivatives was synthesized and evaluated as potent human histamine H₃ receptor inverse agonists. After systematic modification of lead 1a, the potent and selective histamine H₃ inverse agonist 1-(3-{4-[(2S,3S)-8-methoxy-3-methyl-4,4-dioxido-2,3-dihydro-1,4-benzoxathiin-2-yl]phenoxy}propyl)pyrrolidine (5k) was identified. Compound 5k showed good pharmacokinetic profiles and brain penetrability in laboratory animals. After 3 mg/kg oral administration of 5k, significant elevation of brain histamine levels was observed in rats where the brain H₃ receptor was fully occupied.