- INHIBITORS OF CD40-CD154 BINDING
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Disclosed herein are compounds including pharmaceutically acceptable salts, esters, prodrugs, hydrates and tautomers thereof which modulate the interactions of CD-40-CD40L. The compounds are useful for treating, ameliorating or preventing an autoimmune disease, inflammatory disease, or other immune-related disease in a patient in need of treatment.
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Paragraph 00330; 00331; 00332
(2020/10/21)
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- Design, synthesis, and biological evaluation of N-acetyl-2-(or 3-)carboxymethylbenzenesulfonamides as cyclooxygenase isozyme inhibitors
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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.
- Chen, Qiao-Hong,Rao, P. N. Praveen,Knaus, Edward E.
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p. 4694 - 4703
(2007/10/03)
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