Discovery of a 3-pyridylacetic acid derivative (TAK-100) as a potent, selective and orally active dipeptidyl peptidase IV (DPP-4) inhibitor
| Autor: | Yusuke Moritoh, Jason Yano, Shigetoshi Tsubotani, Takuo Kosaka, Yoshihiro Banno, Michiko Amano, Osamu Kataoka, Yasufumi Miyamoto, Koji Takeuchi, Masako Sasaki, Satoru Oi, Tomoko Asakawa, Nobuhiro Suzuki, Akiyoshi Tani, Hiroaki Yashiro, Yoshio Yamamoto, Hironobu Maezaki, Koji Ikedo, Miyuki Funami, Kathleen Aertgeerts, Tohru Yamashita, Tatsuhiko Fujimoto |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Stereochemistry Protein Conformation Pyridines Acetates Crystallography X-Ray Cocrystal Dipeptidyl peptidase Acetic acid chemistry.chemical_compound Structure-Activity Relationship Dogs Catalytic Domain Drug Discovery Pyridine Animals Humans Hypoglycemic Agents Rats Wistar Dipeptidyl peptidase-4 Acid derivative Dipeptidyl-Peptidase IV Inhibitors Quinoline Glucose Tolerance Test Rats Orally active chemistry Quinolines Molecular Medicine Female Hydrophobic and Hydrophilic Interactions |
| Zdroj: | Journal of medicinal chemistry. 54(3) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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