Abstract
The purinoceptor subtypes P2X(3) and P2X(2/3) have been shown to play a pivotal role in models of various pain conditions. Identification of a potent and selective dual P2X(3)/P2X(2/3) diaminopyrimidine antagonist RO-4 prompted subsequent optimization of the template. This paper describes the SAR and optimization of the diaminopyrimidine ring and particularly the substitution of the 2-amino group. The discovery of the highly potent and drug-like dual P2X(3)/P2X(2/3) antagonist RO-51 is presented.
MeSH terms
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Adenosine Triphosphate / chemistry
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Analgesics / chemical synthesis*
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Analgesics / pharmacology*
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Animals
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CHO Cells
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Chemistry, Pharmaceutical / methods*
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Cricetinae
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Cricetulus
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Drug Design
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Drug Evaluation, Preclinical
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Humans
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Inhibitory Concentration 50
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Models, Chemical
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Pain / drug therapy*
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Purinergic P2 Receptor Antagonists*
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacology*
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Receptors, Purinergic P2 / chemistry
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Structure-Activity Relationship
Substances
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Analgesics
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Purinergic P2 Receptor Antagonists
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Pyrimidines
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RO-51 compound
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Receptors, Purinergic P2
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Adenosine Triphosphate