Cyclohexyl-linked tricyclic isoxazoles are potent and selective modulators of the multidrug resistance protein (MRP1)

…, JS Kroin, JD Cohen, LN Jungheim, JJ Starling…

Index: Norman, Bryan H.; Lander, Peter A.; Gruber, Joseph M.; Kroin, Julian S.; Cohen, Jeffrey D.; Jungheim, Louis N.; Starling, James J.; Law, Kevin L.; Self, Tracy D.; Tabas, Linda B.; Williams, Daniel C.; Paul, Donald C.; Dantzig, Anne H. Bioorganic and Medicinal Chemistry Letters, 2005 , vol. 15, # 24 p. 5526 - 5530

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Citation Number: 42

Abstract

Structure–activity relationship (SAR) studies on the tricyclic isoxazole series of MRP1 modulators have resulted in the identification of potent and selective inhibitors containing cyclohexyl-based linkers. These studies ultimately identified compound 21b, which reverses drug resistance to MRP1 substrates, such as doxorubicin, in HeLa-T5 cells (EC50= 0.093 μM), while showing no inherent cytotoxicity. Additionally, 21b inhibits ATP-dependent, ...