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

Novel cyclohexyl drug resistance modulators were synthesized and evaluated for in vitro inhibition of the drug resistance transporter, MRP1. This series resulted in the potent and selective MRP1 modulator 21b, which demonstrated reversal of MRP1-mediated multidrug resistance in vivo. Structure–activ...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2005-12, Vol.15 (24), p.5526-5530
Main Authors: 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.
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Biological and medical sciences
General aspects
HeLa Cells
Humans
Isoxazole
Isoxazoles - chemical synthesis
Isoxazoles - pharmacology
Kinetics
Medical sciences
Molecular Conformation
MRP
Multidrug resistance
Multidrug Resistance-Associated Proteins - antagonists & inhibitors
Pharmacology. Drug treatments
Structure-Activity Relationship
Tricyclic
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Summary:Novel cyclohexyl drug resistance modulators were synthesized and evaluated for in vitro inhibition of the drug resistance transporter, MRP1. This series resulted in the potent and selective MRP1 modulator 21b, which demonstrated reversal of MRP1-mediated multidrug resistance in vivo. 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 (EC 50 = 0.093 μM), while showing no inherent cytotoxicity. Additionally, 21b inhibits ATP-dependent, MRP1-mediated LTC 4 uptake into membrane vesicles prepared from the MRP1-overexpressing HeLa-T5 cells (EC 50 = 0.064 μM) and shows selectivity (1115-fold) against the related transporter, P-glycoprotein, in HL60/Adr and HL60/Vinc cells. Finally, when dosed in combination with the oncolytic MRP1 substrate vincristine, 21b showed tumor regression and growth delay in MRP1-overexpressing tumors in vivo.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2005.08.075