2. Academic Validation
  3. 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

  • J Med Chem. 2011 Feb 10;54(3):831-50. doi: 10.1021/jm101236h.
Yasufumi Miyamoto 1,  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
Affiliations

Affiliation

  • 1 Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-Chome, Osaka 532-8686, Japan.
PMID: 21218817 DOI: 10.1021/jm101236h
Abstract

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.

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