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

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

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 p...

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Bibliographic Details
Published in:ACS medicinal chemistry letters Vol. 14; no. 1; pp. 110 - 115
Main Authors: Kostyo, Jessica H., Lallande, Avery T., Sells, Chloë A., Shuda, Mina R., Kane, Robert R.
Format: Journal Article
Language:English
Published: United States American Chemical Society 12-01-2023
Subjects:
Letter
resatorvid
Prodrug
sulfonamide
TLR4
TAK-242
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Summary: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.
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This paper was originall published ASAP on December 9, 2022. Due to a production error, parts of Scheme 6 were missing. The corrected version was reposted on December 12, 2022.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.2c00492