Structure Report for: 3O95

Yano, J.K., Aertgeerts,K.

Title: Discovery of a 3-pyridylacetic acid derivative (TAK-100) as a potent, selective and orally active dipeptidyl peptidase IV (DPP-4) inhibitor
Miyamoto Y, Banno Y, Yamashita T, Fujimoto T, Oi S, Moritoh Y, Asakawa T, Kataoka O, Yashiro H and Maezaki H <12 more author(s)> 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 (- 12)
Ref: Journal of Medicinal Chemistry, 54:831, 2011 : PubMed
Abstract


ESTHER: Miyamoto_2011_J.Med.Chem_54_831
PubMedSearch: Miyamoto 2011 J.Med.Chem 54 831
PubMedID: 21218817
Gene_locus related to this paper: human-DPP4
Inhibitor(s) related to this paper: TAK-100, TAK-986

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]ac etic 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.