Abstract
In our continued effort to identify selective MRP1 modulators, we have developed two novel templates, 3 and 4, through rational drug design by identifying the key pharmacophore interaction at the 7-position of the pyrrolopyrimidine template 1. Further synthesis and SAR work on these novel templates gave a number of potent MRP1 modulators with great selectivity against Pgp. Additional studies to reduce the CYP3A4 inhibition are also reported. Several compounds of these classes were subjected to in vivo xenograft studies and in vivo efficacies were demonstrated.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
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Animals
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Area Under Curve
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Biological Availability
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Cell Line, Tumor
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Combinatorial Chemistry Techniques
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme Inhibitors
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Doxorubicin / pharmacology
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Drug Resistance, Multiple*
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Drug Synergism
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Female
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Half-Life
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Humans
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Models, Molecular
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Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
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Multidrug Resistance-Associated Proteins / biosynthesis
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Cytochrome P-450 Enzyme Inhibitors
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Multidrug Resistance-Associated Proteins
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Pyrimidines
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Pyrroles
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Doxorubicin
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CYP3A protein, human
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human