| 19140144 |
Colabufo NA, Berardi F, Perrone MG, Cantore M, Contino M, Inglese C, Niso M, Perrone R: Multi-drug-resistance-reverting agents: 2-aryloxazole and 2-arylthiazole derivatives as potent BCRP or MRP1 inhibitors. ChemMedChem. 2009 Feb;4(2):188-95.
2-Aryloxazole and 2-arylthiazole derivatives were evaluated for their inhibitory activity toward P-glycoprotein (P-gp) as well as their selectivity toward other ABC transporters involved in multi-drug resistance such as BCRP and MRP1. These derivatives have 6,7-dimethoxytetrahydroisoquinoline or cyclohexylpiperazine moieties, which are the same basic nuclei of the potent P-gp inhibitors MC70 (EC (50)=0.05 microM) and PB28 (EC (50)=0.55 microM), respectively. The results demonstrate that 2-aryloxazole and 2-arylthiazole derivatives, planned as cycloisosteres of MC70, were found to be less potent than the reference compound in inhibiting P-gp. These compounds were evaluated for their BCRP and MRP1 inhibitory activities. In particular, 6,7-dimethoxytetrahydroisoquinoline derivatives, unsubstituted, 3-Br, 3-Cl, and 3-OCH (3) 2-aryloxalzole derivatives showed the best BCRP inhibitory activity (EC (50) range: 0.24-0.46 microM). In contrast, all cyclohexylpiperazine derivatives except one (EC (50)=0.56 microM), showed decreased BCRP inhibitory activity. All compounds tested were unable to inhibit the MRP1 pump, with the exception of the 2-OCH (3) and 4-OCH (3) derivatives of the 6,7-dimethoxytetrahydroisoquinoline series, which displayed high MRP1 inhibitory activity (EC (50)=0.84 and 0.90 microM, respectively). |
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