Structure-based design of a new class of anti-inflammatory drugs:: secretory phospholipase A2 inhibitors, SPI

Human non-pancreatic secretory phospholipase A(2) (hnps-PLA(2)) is a group IIA enzyme that is massively over-expressed in a variety of severe inflammatory diseases. The enzyme degrades membrane phospholipids and it has been hypothesized that this activity can lead to a loss of tissue and organ integrity and function. This report overviews efforts directed toward the identification and clinical evaluation of a new class of anti-inflammatory drugs that specifically targets and inhibits the catalytic site of this hydrolytic enzyme. To achieve this goal, structure-based drug design was applied to a lead molecule identified by random high volume screening. Through an iterative process consisting of X-ray structure determination followed by inhibitor modification and testing, the lead compound was improved more than 6000-fold. Detailed information learned from earlier X-ray studies of stable substrate mimics aided this inhibitor improvement process. The optimized drug candidate, LY315920/S-5920, is currently undergoing phase II clinical evaluation. The outcome of studies such as these will define with greater clarity the pathological role of hnps-PLA(2) in human inflammatory diseases. (C) 1999 Elsevier Science B.V. All rights reserved.