2. Academic Validation
  3. Tricyclic isoxazoles are novel inhibitors of the multidrug resistance protein (MRP1)

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.
Bryan H Norman 1,  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
Affiliations

Affiliation

  • 1 Discovery Chemistry Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. [email protected]
PMID: 11958985 DOI: 10.1016/s0960-894x(02)00051-3
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.

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