Reversal of P-glycoprotein mediated multidrug resistance by novel anthranilamide derivatives

• Published in: Bioorganic & medicinal chemistry letters Vol. 9; no. 4; pp. 595 - 600
• Main Authors: Roe, Michael, Folkes, Adrian, Ashworth, Philip, Brumwell, Julie, Chima, Lal, Hunjan, Sukhjit, Pretswell, Ian, Dangerfield, Wendy, Ryder, Hamish, Charlton, Peter
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 22.02.1999; Elsevier
• Subjects: Antineoplastic agents; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Biological and medical sciences; Doxorubicin - pharmacology; Drug Resistance, Multiple; Drug Synergism; General aspects; Humans; Medical sciences; ortho-Aminobenzoates - chemistry; ortho-Aminobenzoates - pharmacology; Pharmacology. Drug treatments; Structure-Activity Relationship; Tumor Cells, Cultured; Antineoplastic agent; Nitrogen heterocycle; Lung; P Glycoprotein; Cytotoxicity; Doxorubicin; Daunorubicin; Structure activity relation; Modulation; Multiple resistance; Aromatic compound; Drug interaction; Mammary gland; Inhibition; Chemical synthesis; Tumor cell; Carrier protein; Human; Transmembrane protein; Drug combination; Isoquinoline derivatives; Rodentia; Benzene derivatives; In vitro; In vivo; Vertebrata; Mammalia; Cell line; Mouse; Animal; Benzamide derivatives; Carboxamide; Reversibility; Anthracyclins
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(99)00030-X

We have synthesised and evaluated a series of anthranilamide based modulators of P-glycoprotein. These studies have identified XR9576( 2), a potent inhibitor of P-glycoprotein in vitro and in vivo. The general synthesis and the SAR of these compounds are described. We have synthesised and evaluated a series of anthranilamide based modulators of P-glycoprotein. These studies have identified XR9576( 2), a potent inhibitor of P-glycoprotein in vitro (accumulation assay, IC 50= 38±18 nM) and in vivo. The general synthesis and the SAR of these compounds are described.