title: Cyclohexyl-linked tricyclic isoxazoles are potent and selective modulators of the multidrug resistance protein (MRP1).
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 (EC(50)=0.093microM), 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)=0.064microM) 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.
authors.affiliation: Discovery Chemistry Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. norman@lilly.com
authors.forename: Bryan H
authors.initials: BH
authors.lastname: Norman
authors.forename: Peter A
authors.initials: PA
authors.lastname: Lander
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Gruber
authors.forename: Julian S
authors.initials: JS
authors.lastname: Kroin
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Cohen
authors.forename: Louis N
authors.initials: LN
authors.lastname: Jungheim
authors.forename: James J
authors.initials: JJ
authors.lastname: Starling
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Law
authors.forename: Tracy D
authors.initials: TD
authors.lastname: Self
authors.forename: Linda B
authors.initials: LB
authors.lastname: Tabas
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Williams
authors.forename: Donald C
authors.initials: DC
authors.lastname: Paul
authors.forename: Anne H
authors.initials: AH
authors.lastname: Dantzig
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D007700:Kinetics; D008968:Molecular Conformation; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007555:Isoxazoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1