DISCOVERY OF NEW NON-PHOSPHOLIPID INHIBITORS OF THE SECRETORY PHOSPHOLIPASES A(2)

A novel series of highly potent, nonphospholipid inhibitors of the secreted PLA2s has been discovered. The design of these molecules was based on the hypothesis that the carboxylate function may provide interactions with the active sites of the enzymes which are of similar magnitude to those of the phosphocholine moiety present in molecules which we have previously described. It is likely that such simplified compounds will have improved metabolic stability compared with the phospholipid analogues. There are clearly some significant differences in the inhibitor structure-activity relationships between the pancreatic (group I) and human platelet (group II) enzymes, and these are presently being rationalized in molecular modeling studies using the published X-ray crystal structures of the different proteins. This study provides one of the first examples of the successful use of the carboxylic acid function as a bioisosteric replacement for a phosphodiester group in the rational design of biologically active molecules10. The most potent inhibitor (9b) to be described in this communication has been designated as FPL 67047XX. The compound has an IC50 against the human platelet sPLA2 of 21 ± 4 nM. The properties of this molecule are presently being investigated in animal models with the objective of identifying the role which the group II sPLA2 may play in inflammatory disease. © 1994, American Chemical Society. All rights reserved.