title: 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.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: Joseph M
authors.initials: JM
authors.lastname: Gruber
authors.forename: Sean P
authors.initials: SP
authors.lastname: Hollinshead
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Wilson
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: Margaret M
authors.initials: MM
authors.lastname: Wagner
authors.forename: Anne H
authors.initials: AH
authors.lastname: Dantzig
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004357:Drug Synergism; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017997:Leukotriene C4 / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D004317:Doxorubicin; D006575:Heterocyclic Compounds, 3-Ring; D007555:Isoxazoles; D017997:Leukotriene C4; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014750:Vincristine; C421109:multidrug resistance-associated protein 1