Abstract
In this report, the design and synthesis of a series of pyrimidine based adenosine A(2A) antagonists are described. The strategy and outcome of expanding SAR exploration to attenuate hERG and improve selectivity over A(1) are discussed. Compound 33 exhibited excellent potency, selectivity over A(1), and reduced hERG liability.
MeSH terms
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Adenosine A2 Receptor Antagonists*
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Cell Line
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Cytochrome P-450 CYP3A / metabolism
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Cytochrome P-450 CYP3A Inhibitors
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DNA-Binding Proteins / antagonists & inhibitors*
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Drug Design
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Humans
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Kinetics
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Receptor, Adenosine A2A / metabolism
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Structure-Activity Relationship
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Trans-Activators / antagonists & inhibitors*
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Transcriptional Regulator ERG
Substances
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Adenosine A2 Receptor Antagonists
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Cytochrome P-450 CYP3A Inhibitors
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DNA-Binding Proteins
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ERG protein, human
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Pyrimidines
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Receptor, Adenosine A2A
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Trans-Activators
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Transcriptional Regulator ERG
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human