Discovery of a 3-pyridylacetic acid derivative (TAK-100) as a potent, selective and orally active dipeptidyl peptidase IV (DPP-4) inhibitor.
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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DOI：
10.1021/jm101236h
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发表时间：
2011-01
影响因子：
7.3
通讯作者：
Y. Miyamoto;Yoshihiro Banno;Tohru Yamashita;Tatsuhiko Fujimoto;Satoru Oi;Yusuke Moritoh;T. Asakawa
中科院分区：
文献类型：
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作者：
Y. Miyamoto;Yoshihiro Banno;Tohru Yamashita;Tatsuhiko Fujimoto;Satoru Oi;Yusuke Moritoh;T. Asakawa
抑制二肽基肽酶 IV (DPP-4) 是治疗糖尿病的一种令人兴奋的新方法。迄今为止，还没有具有羧基的 DPP-4 化学型进入临床试验。从结构新颖的喹啉衍生物1的发现出发，我们设计了新型的含有羧基的吡啶衍生物。在我们的设计中，羧基与催化区域周围的目标氨基酸残基相互作用，从而增加了抑制活性。经过进一步优化，我们确定了[5-(氨基甲基)-6-(2,2-二甲基丙基)-2-乙基-4-(4-甲基苯基)吡啶-3-基]乙酸(30c)水合物作为有效的选择性DPP-4抑制剂。通过 X 射线共晶结构分析证实了与关键活性位点残基的所需相互作用，例如与 Arg125 的盐桥相互作用。此外，化合物 30c 显示出所需的临床前安全性，其编码为 TAK-100。
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.