Discovery of novel 4-amino-6-arylaminopyrimidine-5-carbaldehyde oximes as dual inhibitors of EGFR and ErbB-2 protein tyrosine kinases

• Published in: Bioorganic & medicinal chemistry 2008-06, Vol.18 (12), p.3495-3499
• Main Authors: Xu, Guozhang, Searle, Lily Lee, Hughes, Terry V., Beck, Amanda K., Connolly, Peter J., Abad, Marta C., Neeper, Michael P., Struble, Geoffrey T., Springer, Barry A., Emanuel, Stuart L., Gruninger, Robert H., Pandey, Niranjan, Adams, Mary, Moreno-Mazza, Sandra, Fuentes-Pesquera, Angel R., Middleton, Steven A., Greenberger, Lee M.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Binding Sites - drug effects; Bioisostere; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; EGFR; ErbB-2; General aspects; Humans; Hydrogen Bonding; Inhibitory Concentration 50; Medical sciences; Models, Molecular; Molecular Structure; Oxime; Oximes - chemical synthesis; Oximes - chemistry; Oximes - pharmacology; Pharmacology. Drug treatments; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Quinazoline; Rats; Rats, Sprague-Dawley; Receptor tyrosine kinase; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - chemistry; Receptor, ErbB-2 - antagonists & inhibitors; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.05.024

We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC 50 values in the nanomolar range. We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC 50 values in the nanomolar range. Structure–activity relationship (SAR) studies elucidated a critical role for the 4-amino and C-6 arylamino moieties. The X-ray co-crystal structure of EGFR with 37 was determined and validated our design rationale.