Abstract
Synthetic modifications on a 6-furanylquinazoline scaffold to optimize the dual ErbB-1/ErbB-2 tyrosine kinase inhibition afforded consistent SAR whereby a 4-(3-fluorobenzyloxy)-3-haloanilino provided the best enzyme potency and cellular selectivity. Changes made to the 6-furanyl group had little impact on the enzyme activity, but appeared to dramatically affect the cellular efficacy. The discovery of lapatinib emerged from this work.
MeSH terms
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Cell Line, Tumor
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ErbB Receptors / antagonists & inhibitors*
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Furans / chemical synthesis
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Furans / chemistry*
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Furans / pharmacology*
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Humans
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Inhibitory Concentration 50
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Lapatinib
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Models, Molecular
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Molecular Structure
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Quinazolines / chemical synthesis
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Quinazolines / chemistry*
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Quinazolines / pharmacology*
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Receptor, ErbB-2 / antagonists & inhibitors*
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism
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Structure-Activity Relationship
Substances
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Furans
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Protein Kinase Inhibitors
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Quinazolines
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Lapatinib
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ErbB Receptors
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Receptor, ErbB-2