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
  • 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.

Products