Synthesis and Evaluation of Structurally Constrained Quinazolinone Derivatives as Potent and Selective Histamine H3 Receptor Inverse Agonists
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- 作者：Tsuyoshi Nagase ; Takashi Mizutani ; Etsuko Sekino ; Shiho Ishikawa ; Sayaka Ito ; Yuko Mitobe ; Yasuhisa Miyamoto ; Ryo Yoshimoto ; Takeshi Tanaka ; Akane Ishihara ; Norihiro Takenaga ; Shigeru Tokita ; Nagaaki S
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：November 13, 2008
- 年：2008
- 卷：51
- 期：21
- 页码：6889-6901
- 全文大小：221K
- 年卷期：v.51,no.21(November 13, 2008)
- ISSN：1520-4804
文摘
A series of structurally constrained derivatives of the potent H3 inverse agonist 1 was designed, synthesized, and evaluated as histamine H3 receptor inverse agonists. As a result, the N-cyclobutylpiperidin-4-yloxy group as in 2f was identified as an optimal surrogate structure for the flexible 1-pyrrolidinopropoxy group of 1. Subsequent optimization of the quinazolinone core of 2f revealed that substitution at the 5-position of the quinazolinone ring influences potency. Representative derivatives 5a and 5s showed improved potency in a histamine release assay in rats and a receptor occupancy assay in mice.