Design, synthesis, and characterization of linkers that utilize a two-stage release mechanism to improve the delivery of the sulfonamide TLR4 signaling inhibitor TAK-242 (Resatorvid)
Kostyo, J., Lallande, A., Sells, C., Mina R. Shuda, & Kane, R. R. (2023). “Design, synthesis, and characterization of linkers that utilize a two-stage release mechanism to improve the delivery of the sulfonamide TLR4 signaling inhibitor TAK-242 (Resatorvid)” ACS Med Chem Lett. 2023, 14 (1) 110-115.
Abstract: We previously demonstrated that the potent TLR4 inhibitor TAK-242 could be covalently conjugated to pancreatic islets using a linker that afforded an effective sustained delivery of the active drug after transplant. This drug-eluting tissue achieved local inhibition of TLR4-linked inflammation and proved beneficial to the islet graft survival. Here, we describe a new family of prodrugs with a modular design featuring a self-immolative para-aminobenzyl spacer bonded directly to the TAK-242 sulfonamide nitrogen, a tether for bioconjugation, and a β-eliminative arylsulfone “trigger”. The inclusion of the para-aminobenzyl spacer affords a more stable prodrug which exhibits complex drug-release kinetics due to a two-stage release mechanism. This manuscript reports the preparation and characterization of several TAK-242 prodrugs fitted with different triggers and linkers and demonstrates that these second-generation prodrugs effectively release TAK-242 while avoiding nonproductive sulfonamide hydrolysis.