Abstract
The synthesis and pharmacological activity of a series of bicyclic pyrazolo[1,5-a]pyrimidines as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema and air-pouch model). Modification of the pyrimidine substituents showed that 6,7-disubstitution provided the best activity and led to the identification of 3-(4-fluorophenyl)-6,7-dimethyl-2-(4-methylsulfonylphenyl)pyrazolo[1,5-a]pyrimidine (10f) as one of the most potent and selective COX-2 inhibitor in this series.
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Carrageenan
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Cell Line
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Cyclooxygenase 1
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Cyclooxygenase 2
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Edema / drug therapy
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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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Exudates and Transudates / enzymology
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Humans
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Isoenzymes / antagonists & inhibitors*
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Male
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Membrane Proteins
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Prostaglandin-Endoperoxide Synthases
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / 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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Rats, Inbred Lew
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Rats, Sprague-Dawley
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Stomach / enzymology
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Structure-Activity Relationship
Substances
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3-(4-fluorophenyl)-6,7-dimethyl-2-(4-methylsulfonylphenyl)pyrazolo(1,5-a)pyrimidine
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Anti-Inflammatory Agents, Non-Steroidal
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Enzyme Inhibitors
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Isoenzymes
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Membrane Proteins
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Pyrazoles
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Pyrimidines
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Carrageenan
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Cyclooxygenase 1
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Cyclooxygenase 2
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PTGS1 protein, human
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Ptgs1 protein, rat