Synthesis of Nitrile Tak-242 Derivatives and Gemfibrozil Analogs

Abstract

TAK-242 (resatorvid) is a selective antagonist of Toll-like receptor 4 (TLR4) signaling, previously shown to improve transplantation outcomes in a murine model. To further expand the structure-activity relationship of TAK-242, we have synthesized a few analogs of TAK-242. Our approach was to start with a nitrile group in place of the ester to use as a functional handle. These new molecules contain different electron-withdrawing groups on the cyclohexene ring, synthesized from a starting nitrile. This thesis also discusses syntheses of analogs of gemfibrozil, an sGC agonist. To develop a better structure-activity relationship of sGC activators, the aromatic region and carboxylic acid were targeted. The new molecules synthesized are pending biological testing for respective TLR4 inhibition and sGC activation.