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Discovery of a 3-Pyridylacetic Acid Derivative (TAK-100) as a Potent, Selective and Orally Active Dipeptidyl Peptidase IV (DPP-4) Inhibitor
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2011-01-10 00:00:00 , DOI: 10.1021/jm101236h Yasufumi Miyamoto 1 , Yoshihiro Banno 1 , Tohru Yamashita 1 , Tatsuhiko Fujimoto 1 , Satoru Oi 1 , Yusuke Moritoh 1 , Tomoko Asakawa 1 , Osamu Kataoka 1 , Hiroaki Yashiro 1 , Koji Takeuchi 1 , Nobuhiro Suzuki 1 , Koji Ikedo 1 , Takuo Kosaka 1 , Shigetoshi Tsubotani 1 , Akiyoshi Tani 1 , Masako Sasaki 1 , Miyuki Funami 1 , Michiko Amano 1 , Yoshio Yamamoto 1 , Kathleen Aertgeerts 2 , Jason Yano 2 , Hironobu Maezaki 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2011-01-10 00:00:00 , DOI: 10.1021/jm101236h Yasufumi Miyamoto 1 , Yoshihiro Banno 1 , Tohru Yamashita 1 , Tatsuhiko Fujimoto 1 , Satoru Oi 1 , Yusuke Moritoh 1 , Tomoko Asakawa 1 , Osamu Kataoka 1 , Hiroaki Yashiro 1 , Koji Takeuchi 1 , Nobuhiro Suzuki 1 , Koji Ikedo 1 , Takuo Kosaka 1 , Shigetoshi Tsubotani 1 , Akiyoshi Tani 1 , Masako Sasaki 1 , Miyuki Funami 1 , Michiko Amano 1 , Yoshio Yamamoto 1 , Kathleen Aertgeerts 2 , Jason Yano 2 , Hironobu Maezaki 1
Affiliation
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.
中文翻译:
发现3-吡啶基乙酸衍生物(TAK-100)作为有力,选择性和口服活性的二肽基肽酶IV(DPP-4)抑制剂
抑制二肽基肽酶IV(DPP-4)是治疗糖尿病的令人兴奋的新方法。迄今为止,尚无具有羧基的DPP-4化学型已进入临床试验。从发现结构新颖的喹啉衍生物1出发,我们设计了含有羧基的新型吡啶衍生物。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。经过进一步优化后,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]乙酸的水合物(30c)作为有效且选择性的DPP-4抑制剂。通过X射线共晶结构分析确认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表现出所需的临床前安全性,编码为TAK-100。
更新日期:2011-01-10
中文翻译:
![](https://scdn.x-mol.com/jcss/images/paperTranslation.png)
发现3-吡啶基乙酸衍生物(TAK-100)作为有力,选择性和口服活性的二肽基肽酶IV(DPP-4)抑制剂
抑制二肽基肽酶IV(DPP-4)是治疗糖尿病的令人兴奋的新方法。迄今为止,尚无具有羧基的DPP-4化学型已进入临床试验。从发现结构新颖的喹啉衍生物1出发,我们设计了含有羧基的新型吡啶衍生物。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。经过进一步优化后,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]乙酸的水合物(30c)作为有效且选择性的DPP-4抑制剂。通过X射线共晶结构分析确认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表现出所需的临床前安全性,编码为TAK-100。