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

Bioorg Med Chem Lett. 2002 Mar 25;12(6):883-6. doi: 10.1016/s0960-894x(02)00051-3.


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.

MeSH terms

  • 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
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Isoxazoles / chemical synthesis*
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology
  • Leukotriene C4 / metabolism
  • Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • Vincristine / pharmacology


  • 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