Discovery of a 3-Pyridylacetic Acid Derivative (TAK-100) as a Potent, Selective and Orally Active Dipeptidyl Peptidase IV (DPP-4) Inhibitor

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• 作者：Yasufumi Miyamoto ; Yoshihiro Banno ; Tohru Yamashita ; Tatsuhiko Fujimoto ; Satoru Oi ; Yusuke Moritoh ; Tomoko Asakawa ; Osamu Kataoka ; Hiroaki Yashiro ; Koji Takeuchi ; Nobuhiro Suzuki ; Koji Ikedo ; Takuo Kosaka ; Shigetoshi Tsubotani ; Akiyoshi Tani ; Masako Sasaki ; Miyuki Funami ; Michiko Amano ; Yoshio Yamamoto ; Kathleen Aertgeerts ; Jason Yano ; Hironobu Maezaki
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：February 10, 2011
• 年：2011
• 卷：54
• 期：3
• 页码：831-850
• 全文大小：1267K
• 年卷期：v.54,no.3(February 10, 2011)
• ISSN：1520-4804

文摘

Inhibition of dipeptidyl peptidase IV (DPP-4) is an exciting new approach for the treatment of diabetes. To date there has been no DPP-4 chemotype possessing a carboxy group that has progressed into clinical trials. Originating from the discovery of the structurally novel quinoline derivative 1, we designed novel pyridine derivatives containing a carboxy group. In our design, the carboxy group interacted with the targeted amino acid residues around the catalytic region and thereby increased the inhibitory activity. After further optimization, we identified a hydrate of [5-(aminomethyl)-6-(2,2-dimethylpropyl)-2-ethyl-4-(4-methylphenyl)pyridin-3-yl]acetic acid (30c) as a potent and selective DPP-4 inhibitor. The desired interactions with the critical active-site residues, such as a salt-bridge interaction with Arg125, were confirmed by X-ray cocrystal structure analysis. In addition, compound 30c showed a desired preclinical safety profile, and it was encoded as TAK-100.