efipladib has been researched along with Edema* in 2 studies
2 other study(ies) available for efipladib and Edema
| Article | Year |
|---|---|
Design, synthesis, and biological evaluation of 3-(1-Aryl-1H-indol-5-yl)propanoic acids as new indole-based cytosolic phospholipase A2α inhibitors.
This article describes the design, synthesis, and biological evaluation of new indole-based cytosolic phospholipase A2α (cPLA2α, a group IVA phospholipase A2) inhibitors. A screening-hit compound from our library, (E)-3-{4-[(4-chlorophenyl)thio]-3-nitrophenyl}acrylic acid (5), was used to design a class of 3-(1-aryl-1H-indol-5-yl)propanoic acids as new small molecule inhibitors. The resultant structure-activity relationships studied using the isolated enzyme and by cell-based assays revealed that the 1-(p-O-substituted)phenyl, 3-phenylethyl, and 5-propanoic acid groups on the indole core are essential for good inhibitory activity against cPLA2α. Optimization of the p-substituents on the N1 phenyl group led to the discovery of 56n (ASB14780), which was shown to be a potent inhibitor of cPLA2α via enzyme assay, cell-based assay, and guinea pig and human whole-blood assays. It displayed oral efficacy toward mice tetradecanoyl phorbol acetate-induced ear edema and guinea pig ovalbumin-induced asthma models. Topics: Animals; Area Under Curve; Asthma; Cytosol; Dogs; Drug Design; Edema; Enzyme Inhibitors; Female; Group IV Phospholipases A2; Guinea Pigs; Haplorhini; Humans; Indoles; Male; Metabolic Clearance Rate; Mice; Mice, Inbred C57BL; Models, Chemical; Molecular Structure; Ovalbumin; Propionates; Structure-Activity Relationship; Tetradecanoylphorbol Acetate; U937 Cells | 2014 |
Indole cytosolic phospholipase A2 alpha inhibitors: discovery and in vitro and in vivo characterization of 4-{3-[5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid, efipladib.
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 | 2008 |