pyrrophenone and Asthma

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