sc-560 and Edema

A series of 2-phenyl-4,5,6,7-tetrahydro[b]benzothiophene derivatives were synthesized and evaluated for in vitro COX inhibitory potential. Within the series, compounds 4a, 4j, 4k, and 4q were identified as potential and selective COX-2 inhibitors with COX-2 IC

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cyclooxygenase 2 Inhibitors; Drug Design; Edema; Mice; Molecular Docking Simulation; Rats; RAW 264.7 Cells; Thiophenes

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Edema; Granuloma; Molecular Docking Simulation; Molecular Structure; Oxadiazoles; Oximes; Rats; Structure-Activity Relationship; Ulcer

In this study, eighteen new isoxazolo[4,5-d]pyridazin-4(5H)-one derivatives possessing either a 1,3,4-thiadiazole or a 1,2,4-triazole-5-thione moiety were synthesized and tested for anti-inflammatory activity in vitro (COX-1/COX-2, 5-LOX) and in vivo (rat paw edema assay). Compounds 15, 16, 25, 26 and 28-30 showed dual COX-2 (IC(50)'s in the 2.1-10.9 μM range), and 5-LOX (IC(50)'s in the 6.3-63.5 μM range) inhibitory activity. When administered orally to rats, dual COX-2/5-LOX inhibitors showed higher anti-inflammatory activity in vivo (30-45% reduction of the inflammatory response) than the reference drug ibuprofen (18%). Among dual COX-2/5-LOX inhibitors, the most potent compound (28) exhibited the best anti-inflammatory profile by inhibiting both COX-2 (IC(50)=2.1 μM) and 5-LOX (IC(50)=6.3 μM) enzymes. We investigated the binding interactions of compound 28 by an enzyme-ligand molecular modeling (docking) studies, which showed favorable binding interactions in both COX-2 and 5-LOX active sites. Furthermore, the dual acting COX-2/5-LOX compound 28 exhibited a superior gastrointestinal safety profile (ulcer index=0.25) compared to the reference drug ibuprofen (UI=7.0) when administered orally at the same molar dose. These observations suggest that isoxazolo[4,5-d]pyridazin-4(5H)-one analogs represent a new scaffold to design potent, effective, and safe anti-inflammatory agents possessing dual COX-2/5-LOX inhibitory activity.

Topics: Animals; Anti-Inflammatory Agents; Arachidonate 5-Lipoxygenase; Binding Sites; Catalytic Domain; Computer Simulation; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Edema; Enzyme Activation; Humans; Isoxazoles; Lipoxygenase Inhibitors; Protein Binding; Pyridazines; Rats

The optimization of a class of indole cPLA 2 alpha inhibitors is described herein. The importance of the substituent at C3 and the substitution pattern of the phenylmethane sulfonamide region are highlighted. Optimization of these regions led to the discovery of 111 (efipladib) and 121 (WAY-196025), which are shown to be potent, selective inhibitors of cPLA 2 alpha in a variety of isolated enzyme assays, cell based assays, and rat and human whole blood assays. The binding of these compounds has been further examined using isothermal titration calorimetry. Finally, these compounds have shown efficacy when dosed orally in multiple acute and chronic prostaglandin and leukotriene dependent in vivo models.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Benzoates; Biological Availability; Bronchoconstriction; Calorimetry; Carrageenan; Cell Line; Cyclooxygenase 2 Inhibitors; Edema; Group IV Phospholipases A2; Humans; In Vitro Techniques; Isoenzymes; Male; Mice; Protein Binding; Rats; Rats, Sprague-Dawley; Sheep; Structure-Activity Relationship; Sulfonamides

The synthesis of several coumarin Mannich bases is described. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. Their lipophilicity was determined experimentally by RPTLC method. All compounds were evaluated for their antiinflammatory and antioxidant activity and for their ability to inhibit in vitro lipoxygenase. The derivatives were found to present antioxidant and antiinflammatory activities. The tested derivatives inhibited carraggeenin-induced hind paw edema. They also significantly suppressed the arthritis induced by Freund's adjuvant. Compound 10, the most active in vivo, was found to possess protective properties against adjuvant-induced arthritis in rats. The biological in vitro activities were concentration dependent. Hydrophilicity, the presence of a free 7-OH, and steric requirements for the substituent at position 8 are the most important factors in terms of SAR. An attempt was made to correlate several physicochemical properties of the molecules with their in vivo/in vitro activity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Carrageenan; Coumarins; Cyclooxygenase Inhibitors; Edema; Female; Free Radical Scavengers; Immunologic Factors; Lipoxygenase Inhibitors; Male; Mannich Bases; Rats; Rats, Inbred F344; Structure-Activity Relationship; Superoxides