A Practical, Nenitzescu-Based Synthesis of LY311727, the First Potent and Selective s-PLA_2 Inhibitor

摘要

Patients with acute pancreatitis, bacterial peritonitis, adult respiratory distress syndrome (ARDS), septic shock, and arthritis all display extraordinarily high blood levels of secretory phospholipase A_2 (s-PLA_2). The in vivo trigger for s-PLA_2 release under such conditions is mediated by a number of mechanisms, all of which have been investigated as a primary site for drug discovery. However, it is believed that potent and selective inhibitors of s-PLA_2 itself will provide important clinical therapies. A significant study on the structure of human nonpancreatic s-PLA_2 revealed the native crystal form, as well as that complexed with a phosphonate transition state analogue. The former structural information afforded an elegant example of a contemporary structure-based search for selective s-PLA_2 inhibitors, optimally resulting in exciting clinical candidates. From that study, LY311727 (1) emerged as the first potent and selective inhibitor of human nonpancreatic s-PLA_2. The exciting in vitro activity of LY311727 signified that an effective synthesis was warranted to support further in vivo studies.