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Aim:To design and synthesize a series of novel amino acid-binding 1,5-diarylpyrazole derivatives,which are intended to act as prodrugs with better aque-ous solubility than celecoxib,and which will exert potent anti-inflammatory activi-ties after being converted to their parent compounds in vivo.Methods:To intro-duce an amino acid,celecoxib analogs containing amino or methylamino groupwere synthesized first through multi-step chemical reactions.All the synthesizedcompounds were screened in an intact cell-based assay in vitro and in carrag-eenan-induced mouse paw edema in vivo.Some active compounds were selectedfor further evaluation in a carrageenan-induced rat paw edema model.The prelimi-nary pharmacokinetics experiments were conducted using high performance liq-uid chromatography/mass spectrometry(HPLC/MS).Results:Celecoxib,6 of the1,5-diarylpyrazole class of celecoxib analogs,and their amino acid derivatives(hydrochloride salts)were synthesized.In vitro screening,the hydrochloridesalts showed decreased inhibitory effects on cyclooxygenase(COX)-1 and COX-2 compared with their parent compounds,but some exhibited potent anti-inflam-matory activity in vivo.Compound 4a was selected for further evaluation,and itsanti-inflammatory effect was equivalent to that of celecoxib after oral administra-tion in the carrageenan-induced rat paw edema model.At three doses(25 mg/kg,50 mg/kg,and 100 mg/kg)the percentage inhibition on edema was 20.7%,52.6%,and 62.6%(for compound 4a)and 27.8%,38.4%,and 40.1%(for celecoxib),respectively.Preliminary pharmacokinetic evaluations support the hypothesisthat compound 4a was actually converted to its parent compound,compound 4.Conclusion:The compound bound with amino acid acts like prodrug,which canexert anti-inflammatory effect similar to celecoxib after being converted to its par-ent compound.This finding will be of great benefit in carrying out structuralmodifications of prodrug-like selective COX-2 inhibitors.
Aim: To design and synthesize a series of novel amino acid-binding 1,5-diarylpyrazole derivatives, which are intended to act as prodrugs with better aque-ous solubility than celecoxib, and which will exert potent anti-inflammatory activi- ties after being converted to their parent compounds in vivo. Methods: To intro-duce an amino acid, celecoxib analogs containing amino or methylamino groupwere synthesized first through multi-step chemical reactions. All the synthesized compounds were screened in an intact cell-based assay in vitro and in carrag-eenan-induced mouse paw edema in vivo. active compounds were selected for further evaluation in a carrageenan-induced rat paw edema model. The prelimi-nary pharmacokinetics experiments were conducted using high performance liq-uid chromatography / mass spectrometry (HPLC / MS Results: Celecoxib, 6 of the 1, 5-diarylpyrazole class of celecoxib analogs, and their amino acid derivatives (hydrochloride salts) were synthesized. In vitro screening, the hydrochloridesal ts showed decreased inhibitory effects on cyclooxygenase (COX) -1 and COX-2 compared with their parent compounds, but some exhibited potent anti-inflammatory activity in vivo. Compounded 4a was selected for further evaluation, and itsanti-inflammatory effect was equivalent to that of celecoxib after oral administration of the carrageenan-induced rat paw edema model. At three doses (25 mg / kg, 50 mg / kg, and 100 mg / kg) the percentage inhibition on edema was 20.7%, 52.6% , and 62.6% (for compound 4a) and 27.8%, 38.4%, and 40.1% (for celecoxib), respectively. Preliminary pharmacokinetic evaluations support the hypothesisthat compound 4a was actually converted to its parent compound, compound 4.Conclusion: The compound bound with amino acid acts like prodrug, which canexert anti-inflammatory effect similar to celecoxib after being converted to its par- ent compound. This finding will be of great benefit in carrying out structuralmodifications of prodrug-like selective COX-2 inhibitors.