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Discovery of 1,2,4-triazine derivatives as adenosine A(2A) antagonists using structure based drug design.

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.

SUBMITTER: Congreve M 

PROVIDER: S-EPMC3308197 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Discovery of 1,2,4-triazine derivatives as adenosine A(2A) antagonists using structure based drug design.

Congreve Miles M   Andrews Stephen P SP   Doré Andrew S AS   Hollenstein Kaspar K   Hurrell Edward E   Langmead Christopher J CJ   Mason Jonathan S JS   Ng Irene W IW   Tehan Benjamin B   Zhukov Andrei A   Weir Malcolm M   Marshall Fiona H FH  

Journal of medicinal chemistry 20120127 5

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 o  ...[more]

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