Bioorganic and Medicinal Chemistry p. 4694 - 4703 (2005)
Update date:2022-08-04
Topics: Optimization Structure-Activity Relationship (SAR) Analysis Chemical Synthesis Animal Studies Literature Review Biological Evaluation Molecular Design Target Identification and Assay Development Toxicity and Safety Assessment Clinical Trials (if applicable) Data Analysis and Reporting Intellectual Property and Patents
Chen, Qiao-Hong
Rao, P. N. Praveen
Knaus, Edward E.
A group of N-acetyl-2-(or 3-)carboxymethylbenzenesulfonamides, possessing either a F or a substituted-phenyl ring substituent (4-F, 2,4-F2, 4-SO2Me, 4-OCHMe2) attached to its C-4 or C-6 position, was prepared using a palladium-catalyzed Suzuki cross-coupling reaction for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. Although N-acetyl-3-carboxymethyl-6-fluorobenzenesulfonamide [14, COX-1 IC50 = 2.26 μM; COX-2 IC50 = 0.012 μM; COX-2 selectivity index (SI) = 188] and N-acetyl-3-carboxymethyl-6-(4-isopropoxyphenyl)benzenesulfonamide (20c, COX-1 IC50 >100 μM; COX-2 IC50 = 0.15 μM; COX-2 SI >667) exhibited potent in vitro COX-2 inhibitory activity and high COX-2 selectivity, both compounds were inactive anti-inflammatory agents in a carrageenan-induced rat paw edema assay. In contrast, the less potent and less selective COX-2 inhibitors N-acetyl-2-carboxymethyl-4-fluorobenzenesulfonamide (12, COX-1 IC50 = 4.25 μM; COX-2 IC50 = 0.978 μM; COX-2 SI = 4.3), N-acetyl-2-carboxymethyl-4-(2,4-difluorophenyl) benzenesulfonamide (17c, COX-1 IC50 = 1.02 μM; COX-2 IC 50 = 1.00 μM; COX-2 SI = 1.02), and N-acetyl-3-carboxymethyl-6-(4- methanesulfonylphenyl)benzenesulfonamide (20e, COX-1 IC50 = 0.109 μM; COX-2 IC50 = 1.14 μM; COX-2 SI = 0.095) exhibited moderate anti-inflammatory activity where a 75 mg/kg oral dose reduced inflammation 26%, 14%, and 20%, respectively, at 3 h postdrug administration relative to the reference drug aspirin where a 50 mg/kg oral dose reduced inflammation by 25% at 3 h postdrug administration.
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