Abstract
Adenosine (ADO) is an extracellular signaling molecule within the central and peripheral nervous system. Its concentration is increased at sites of tissue injury and inflammation. One of the mechanisms by which antinociceptive and antiinflammatory effects of ADO can be enhanced consists of inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO. Novel nonnucleoside AK inhibitors based on 4-amino-6-alkynylpyrimidines were prepared, and the importance of the length of the linker at the 5-position for high affinity AK inhibition was demonstrated. Compounds with 2- and 3-atom linkers were the most potent AK inhibitors. Optimization of their physicochemical properties led to 31a and 37a that effectively reduced pain and inflammation in animal models.
MeSH terms
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Adenosine / metabolism
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Adenosine Kinase / antagonists & inhibitors*
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Analgesics / chemical synthesis
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Analgesics / chemistry
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Analgesics / pharmacology
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Animals
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / pharmacology
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Humans
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Magnetic Resonance Spectroscopy
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Models, Molecular
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Morpholines / chemical synthesis*
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Morpholines / chemistry
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Morpholines / pharmacology
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Pain Measurement
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Phosphorylation
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Rats
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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4-amino-5-((2-chlorobenzyl)methylamino)-6-(6-(4-morpholinyl)-3-pyridinylethynyl)pyrimidine
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4-amino-5-(benzylmethylaminomethyl)-6-(6-(4-morpholinyl)-3-pyridinylethynyl)pyrimidine
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Analgesics
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Anti-Inflammatory Agents
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Enzyme Inhibitors
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Morpholines
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Pyridines
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Pyrimidines
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Adenosine Kinase
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Adenosine