Design, Synthesis, and Characterization of Prodrugs of Sulfonamide TLR4 Signaling Inhibitor TAK-242 (Resatorvid)

We have previously reported two prodrug designs for the delivery of the potent TLR4 inhibitor TAK-242. Our initial design was used to covalently link TAK-242 to pancreatic islets using a linker to afford sustained delivery of the active drug after transplant. Those drug-eluting islets provided local inhibition of TLR4-linked inflammation and improved islet graft survival. Here, we describe a third family of TAK-242 prodrugs featuring two rate modulating sites, a self-immolative aniline-stabilized methylene spacer bonded directly to the sulfonamide nitrogen, an alcohol tether for bioconjugation, and a β-eliminative aryl-sulfone “trigger”. These prodrugs rapidly release TAK-242 after activation by β-elimination and a rapid subsequent 1,2-elimination, cleanly releasing the drug without detectable intermediates. This manuscript reports the preparation and characterization of a series of methylene-linked TAK-242 prodrugs, evaluating the impact of various modifications on drug release kinetics.