Open AccessDesign and Catalyzed Activation of Tak-242 Prodrugs for Localized Inhibition of TLR4-Induced Inflammation
Author(s) -
Michael A. Plunk,
Alyssa Alaniz,
Olatunde P. Olademehin,
Thomas L. Ellington,
Kevin L. Shuford,
Robert R. Kane
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00518
Subject(s) - prodrug , tlr4 , inflammation , chemistry , nitroreductase , pharmacology , catalysis , drug , enzyme , toll like receptor , receptor , biochemistry , innate immune system , medicine , immunology
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 Pd 0 .