Design and Catalyzed Activation of Tak-242 Prodrugs for Localized Inhibition of TLR4-Induced Inflammation
Michael A. Plunk, Alyssa Alaniz, Olatunde P. Olademehin, Thomas L. Ellington, Kevin L. Shuford, Robert R. Kane
Abstract
Tak-242 (resatorvid), a Toll-like Receptor 4 (TLR4) inhibitor, has been identified as a potent suppressor of innate inflammation. As a strategy to target Tak-242 to select tissue, four TLR4-inactive prodrugs were synthesized for activation via two different release mechanisms. Two nitrobenzyl Tak-242 prodrugs released the parent drug upon exposure to the exogenous enzyme nitroreductase, while the two propargyl prodrugs were converted to Tak-242 in the presence of Pd0.
Topics & Concepts
ProdrugTLR4InflammationChemistryNitroreductaseEnzymePharmacologyDrugCatalysisToll-like receptorReceptorBiochemistryInnate immune systemMedicineImmunologyChemical Synthesis and AnalysisInflammatory mediators and NSAID effectsClick Chemistry and Applications