Sulfonamide Prodrugs with a Two-Stage Release Mechanism for the Efficient Delivery of the TLR4 Antagonist TAK-242

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.

A novel bioresponsive self-immolative spacer based on aza-quinone methide reactivity for the controlled release of thiols, phenols, amines, sulfonamides or amides

“…Recently, the release of resatorvid (TAK-242), a drug containing a sulphonamide group with p K a 8.0–8.1 was reported to occur using a PABA-like linker. 31 Finally, aromatic or aliphatic amines have very low nucleofugacity and release by a self-immolative process occurs only after conversion to the corresponding carbamates. The only exception is the release of tertiary amines from the corresponding quaternary ammonium salt obtained by alkylation with a PABA-Cl derivative.…”