Abstract
Some N-phenyl- (7a-10a) and N-benzyl-substituted (7b-10b) amido analogs of cyclooxygenase (COX-2) selective tricyclic non-steroidal anti-inflammatory drugs have been synthesized with the aim to obtain information on the structural requirements for the COX-inhibitory activity. Compounds 7-10 were tested in vitro for their inhibitory properties only towards COX-2 enzyme by measuring prostaglandin E2 (PGE2) production on activated J774.2 macrophages. Some of the new compounds (7a, 8a, 9a and 9b) showed a modest activity, with percentage inhibition values near 30% at a concentration of 10 microM. These data have been tentatively explained by a conformational study which indicates that at least the N-phenyl-substituted amides 7a-9a present steric hindrances which may prevent a good interaction with COX-2 active site.
MeSH terms
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Amides / chemical synthesis*
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Amides / chemistry
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Amides / pharmacology*
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Animals
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / chemical synthesis*
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Cyclooxygenase Inhibitors / chemistry
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Cyclooxygenase Inhibitors / pharmacology*
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Dinoprostone / biosynthesis
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Drug Design
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Drug Evaluation, Preclinical
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Humans
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Isoenzymes / antagonists & inhibitors*
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Isoxazoles / chemical synthesis
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Isoxazoles / chemistry
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Isoxazoles / pharmacology
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Macrophages / drug effects
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Macrophages / enzymology
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Membrane Proteins
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Molecular Conformation
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Molecular Structure
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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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Structure-Activity Relationship
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Thiophenes / chemical synthesis
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Thiophenes / chemistry
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Thiophenes / pharmacology
Substances
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Amides
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Isoenzymes
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Isoxazoles
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Membrane Proteins
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Pyrazoles
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Thiophenes
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Dinoprostone