Discovery of 1,2,4-triazine derivatives as adenosine A2A antagonists using structure based drug design

Miles Congreve, Stephen P Andrews, Andrew S Dore, Kaspar Hollenstein, Edward Hurrell, Christopher J Langmead, Jonathon S Mason, Irene W Ng, Benjamin G Tehan, Andrei Zhukov, Malcolm Weir, Fiona H Marshall

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Abstract

Potent, ligand efficient, selective, and orally efficacious 1,2,4-triazine derivatives have been identified using structure based drug design approaches as antagonists of the adenosine A 2A receptor. The X-ray crystal structures of compounds 4e and 4g bound to the GPCR illustrate that the molecules bind deeply inside the orthosteric binding cavity. In vivo pharmacokinetic and efficacy data for compound 4k are presented, demonstrating the potential of this series of compounds for the treatment of Parkinson s disease.
Original languageEnglish
Pages (from-to)1898 - 1903
Number of pages6
JournalJournal of Medicinal Chemistry
Volume55
Issue number5
DOIs
Publication statusPublished - 2012
Externally publishedYes

Cite this

Congreve, M., Andrews, S. P., Dore, A. S., Hollenstein, K., Hurrell, E., Langmead, C. J., Mason, J. S., Ng, I. W., Tehan, B. G., Zhukov, A., Weir, M., & Marshall, F. H. (2012). Discovery of 1,2,4-triazine derivatives as adenosine A2A antagonists using structure based drug design. Journal of Medicinal Chemistry, 55(5), 1898 - 1903. https://doi.org/10.1021/jm201376w