Chromatographic resolution, chiroptical characterization and preliminary pharmacological evaluation of the enantiomers of butibufen: a comparison with ibuprofen.
Enantiomeric resolution of butibufen has been achieved on a cellulose tris(3,5-dimethylphenylcarbamate) chiral stationary phase with hexane-isopropanol-trifluoroacetic acid, 100:1.2:0.02 (v/v/v) as mobile phase at a flow rate of 1.0 mL min(-1). Semi-preparative isolation of the enantiomers then chiroptical characterization indicated that the order of elution was (-)-R- before (+)-S-butibufen. When tested for their effects on the cyclooxygenase and 5-lipoxygenase pathways of eicosanoid metabolism in calcium ionophore-activated rat peritoneal leukocytes it was found that (+)-S-butibufen inhibited generation of thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) (cyclooxygenase pathway), with an IC50 of 1.5 microM (approx.), whereas the (-)-R enantiomer was essentially inactive. Neither enantiomer inhibited the 5-lipoxygenase pathway. In this regard, (+)-S-butibufen was approximately five times less potent as a cyclooxygenase inhibitor than (+)-S-ibuprofen. These results show the enantiomeric specificity and pathway selectivity of this novel non-steroidal anti-inflammatory drug.
Hoult
J R
JR
Division of Pharmacology and Therapeutics, King's College London, UK.
Jackson
B R
BR
Benicka
E
E
Patel
B K
BK
Hutt
A J
AJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000187:drug effects / Q000378:metabolism; D001095:Arachidonic Acids / Q000378:metabolism; D001202:Ascitic Fluid / Q000166:cytology; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015777:Eicosanoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007052:Ibuprofen / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D010654:Phenylbutyrates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D004791:Enzyme Inhibitors; D010654:Phenylbutyrates; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; C012797:butibufen; D007052:Ibuprofen