title: Structure-based design of a new class of anti-inflammatory drugs: secretory phospholipase A(2) inhibitors, SPI.
abstract: 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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, IN 46285, USA. mihelich@lilly.com
authors.forename: E D
authors.initials: ED
authors.lastname: Mihelich
authors.forename: R W
authors.initials: RW
authors.lastname: Schevitz
mesh_terms: D000085:Acetates / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D007651:Keto Acids; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000085:Acetates; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D007211:Indoles; D007651:Keto Acids; C117948:varespladib; D010741:Phospholipases A