3O95

Crystal Structure of Human DPP4 Bound to TAK-100

Summary for 3O95

• Entry DOI: 10.2210/pdb3o95/pdb
• Related: 3O9V
• Related PRD ID: PRD_900017
• Descriptor: Dipeptidyl peptidase 4, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: protease and 8-bladed beta-propeller domain, aminopeptidase, cell membrane, glycoprotein, hydrolase, membrane, protease, secreted, serine protease, signal-anchor, transmembrane, signaling protein, signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 350774.62

Authors

Yano, J.K.,Aertgeerts, K. (deposition date: 2010-08-03, release date: 2011-01-26, Last modification date: 2024-10-16)

Primary citation

Miyamoto, Y.,Banno, Y.,Yamashita, T.,Fujimoto, T.,Oi, S.,Moritoh, Y.,Asakawa, T.,Kataoka, O.,Yashiro, H.,Takeuchi, K.,Suzuki, N.,Ikedo, K.,Kosaka, T.,Tsubotani, S.,Tani, A.,Sasaki, M.,Funami, M.,Amano, M.,Yamamoto, Y.,Aertgeerts, K.,Yano, J.,Maezaki, H.
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., 53:3517-3531, 2011

PubMed 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.

PubMed: 21218817
DOI: 10.1021/jm101236h

Experimental method

X-RAY DIFFRACTION (2.85 Å)