A new series of neutral 5-substituted 4-anilinoquinazolines as potent, orally active inhibitors of erbB2 receptor tyrosine kinase

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 2; pp. 674 - 678
• Main Authors: Barlaam, Bernard, Ballard, Peter, Bradbury, Robert H., Ducray, Richard, Germain, Hervé, Hickinson, D. Mark, Hudson, Kevin, Kettle, Jason G., Klinowska, Teresa, Magnien, Françoise, Ogilvie, Donald J., Olivier, Annie, Pearson, Stuart E., Scott, James S., Suleman, Abid, Trigwell, Cath B., Vautier, Michel, Whittaker, Robin D., Wood, Robin
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.01.2008; Elsevier
• Subjects: Administration, Oral; Anilinoquinazoline; Animals; Antineoplastic agents; Biological and medical sciences; C-5 substitution; Cell Line; erbB2 kinase inhibitor; General aspects; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Neoplasm Transplantation; Pharmacology. Drug treatments; Phosphorylation; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Quinazolines - administration & dosage; Quinazolines - chemistry; Quinazolines - pharmacokinetics; Quinazolines - pharmacology; Receptor, ErbB-2 - antagonists & inhibitors; Structure-Activity Relationship; C-5 substitution; Anilinoquinazoline; erbB2 kinase inhibitor; Antineoplastic agent; Intravenous administration; Rat; Nitrogen heterocycle; Quinazoline derivatives; erbB2 Gene; Cytotoxicity; Pyridine derivatives; Signal transduction; Structure activity relation; Bicyclic compound; Aromatic compound; Chemical synthesis; Tumor cell; Human; Ether; Enzyme; Transferases; Rodentia; Oral administration; Enzyme inhibitor; Epidermis; Aniline derivatives; Malignant tumor; In vitro; In vivo; Vertebrata; Chemotherapy; Growth factor receptor; Mammalia; Treatment; Cell line; Mouse; Animal; KB cell line; Carboxamide; Onc gene; Pharmacokinetics; Cancer
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2007.11.052

Starting from initial lead 1 containing a basic 5-substituent, optimisation of the glycolamide-derived neutral 5-substituent led to potent inhibitors of erbB2 with good pharmacokinetics. Representative compounds 19 and 21 inhibited phosphorylation of erbB2 in a mouse BT474C xenograft model after oral administration. Starting from initial lead 1 containing a basic 5-substituent, optimisation of the glycolamide-derived neutral 5-substituent led to potent inhibitors of erbB2 with good pharmacokinetics. Representative compounds 19 and 21 inhibited phosphorylation of erbB2 in a mouse BT474C xenograft model after oral administration.