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.
MeSH terms
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Adenosine A2 Receptor Antagonists / chemical synthesis*
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Adenosine A2 Receptor Antagonists / pharmacokinetics
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Adenosine A2 Receptor Antagonists / pharmacology
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Administration, Oral
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Animals
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Antiparkinson Agents / chemical synthesis*
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Antiparkinson Agents / pharmacokinetics
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Antiparkinson Agents / pharmacology
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Crystallography, X-Ray
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Drug Design
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Humans
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Models, Molecular
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Protein Conformation
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Pyridines / chemical synthesis*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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Radioligand Assay
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Rats
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Receptor, Adenosine A2A / metabolism*
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Structure-Activity Relationship
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Surface Plasmon Resonance
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Triazines / chemical synthesis*
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Triazines / pharmacokinetics
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Triazines / pharmacology
Substances
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6-(2-methyl-6-(trifluoromethyl)pyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine
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Adenosine A2 Receptor Antagonists
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Antiparkinson Agents
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Pyridines
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Receptor, Adenosine A2A
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Triazines