Tricyclic isoxazoles are novel inhibitors of the multidrug resistance protein (MRP1).

Abstract

Tricyclic isoxazoles were identified from a screen as a novel class of selective multidrug resistance protein (MRP1) inhibitors. From a screen lead, SAR efforts resulted in the preparation of LY 402913 (9h), which inhibits MRP1 and reverses drug resistance to MRP1 substrates, such as doxorubicin, in HeLa-T5 cells (EC(50)=0.90 microM), while showing no inherent cytotoxicity. Additionally, LY 402913 inhibits ATP-dependent, MRP1-mediated LTC(4) uptake into membrane vesicles prepared from the MRP1-overexpressing HeLa-T5 cells (EC(50)=1.8 microM). LY 402913 also shows selectivity ( approximately 22-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, LY 402913 delays the growth of MRP1-overexpressing tumors in vivo.

• Authors: Bryan H Norman, Joseph M Gruber, Sean P Hollinshead, Joseph W Wilson, James J Starling, Kevin L Law, Tracy D Self, Linda B Tabas, Daniel C Williams, Donald C Paul, Margaret M Wagner, Anne H Dantzig
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 12 Issue 6 Pg. 883-6 (Mar 25 2002) ISSN: 0960-894X [Print] England
• PMID: 11958985 (Publication Type: Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents, Phytogenic
• Heterocyclic Compounds, 3-Ring
• Isoxazoles
• Multidrug Resistance-Associated Proteins
• Leukotriene C4
• Vincristine
• Doxorubicin
• multidrug resistance-associated protein 1

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Biological Transport, Active (drug effects)
• Cell Division (drug effects)
• Doxorubicin (pharmacology)
• Drug Resistance
• Drug Synergism
• Heterocyclic Compounds, 3-Ring (chemical synthesis, chemistry, pharmacology)
• Humans
• Isoxazoles (chemical synthesis, chemistry, pharmacology)
• Leukotriene C4 (metabolism)
• Multidrug Resistance-Associated Proteins (antagonists & inhibitors)
• Structure-Activity Relationship
• Tumor Cells, Cultured
• Vincristine (pharmacology)