Discovery of 1,2,4-triazine derivatives as adenosine A(2A) antagonists using structure based drug design.
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.
Heptares Therapeutics Limited, BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, UK. miles.congreve@heptares.com
Miles
M
Congreve
Stephen P
SP
Andrews
Andrew S
AS
Doré
Kaspar
K
Hollenstein
Edward
E
Hurrell
Christopher J
CJ
Langmead
Jonathan S
JS
Mason
Irene W
IW
Ng
Benjamin
B
Tehan
Andrei
A
Zhukov
Malcolm
M
Weir
Fiona H
FH
Marshall
D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D014227:Triazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
C573285:6-(2-methyl-6-(trifluoromethyl)pyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D011725:Pyridines; D043705:Receptor, Adenosine A2A; D014227:Triazines