Atropisomeric 4-Phenyl-4H-1,2,4-triazoles as Selective Glycine Transporter 1 Inhibitors

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• 作者：Takashi Sugane ; Takahiko Tobe ; Wataru Hamaguchi ; Itsuro Shimada ; Kyoichi Maeno ; Junji Miyata ; Takeshi Suzuki ; Tetsuya Kimizuka ; Shuichi Sakamoto ; Shin-ichi Tsukamoto
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 25, 2013
• 年：2013
• 卷：56
• 期：14
• 页码：5744-5756
• 全文大小：486K
• 年卷期：v.56,no.14(July 25, 2013)
• ISSN：1520-4804

文摘

We report on the optimization of 4H-1,2,4-triazole derivatives to increase their activity and selectivity as glycine transporter 1 (GlyT1) inhibitors. Structure鈥揳ctivity relationship exploration resulted in the identification of a 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile (14u) compound with markedly higher selectivity for GlyT1. Physiochemical studies revealed that 14u exists as a stable pair of atropisomers under physiological conditions. We successfully separated the atropisomers to obtain active enantiomer (R)-14u, which displayed favorable pharmacokinetic properties, as well as positive results in the mice Y-maze test.