Discovery of novel 5-alkynyl-4-anilinopyrimidines as potent, orally active dual inhibitors of EGFR and Her-2 tyrosine kinases

• Published in: Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (1), p.456-460
• Main Authors: Suzuki, Naoyuki, Shiota, Takeshi, Watanabe, Fumihiko, Haga, Norihiro, Murashi, Takami, Ohara, Takafumi, Matsuo, Kenji, Omori, Naoki, Yari, Hiroshi, Dohi, Keiji, Inoue, Makiko, Iguchi, Motofumi, Sentou, Jyunko, Wada, Tooru
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antitumor efficacy; Biological and medical sciences; BT474; Chemistry, Pharmaceutical - methods; Drug Design; Drug Screening Assays, Antitumor - methods; EGFR; Enzyme Inhibitors - pharmacology; Her-2; Humans; Hydrogen-Ion Concentration; Inhibitory Concentration 50; Kinase inhibitor; Medical sciences; Mice; Microsomes, Liver - metabolism; Models, Chemical; N87; Neoplasm Transplantation; Pharmacology. Drug treatments; phosphotransferases (kinases); Pyrimidine; Pyrimidines - chemistry; Rats; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - chemistry; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - chemistry; Structure-Activity Relationship; structure-activity relationships; tyrosine
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.10.103

5-Alkenyl or 5-alkynyl-4-anilinopyrimidines were prepared and evaluated for in vitro inhibition of EGFR/Her-2 kinase activity and the growth of tumor cell lines (BT474 and N87). Several of these compounds inhibited the growth of BT474 and N87 at concentrations below 200nM. Structure–activity relationship studies revealed a critical role for the 5-alkynyl moieties. The representative compound 19 exhibited significant antitumor potency in a mouse xenograft model. 5-Alkenyl or 5-alkynyl-4-anilinopyrimidines were prepared and evaluated for in vitro inhibition of EGFR/Her-2 kinase activity and the growth of tumor cell lines (BT474 and N87). Several of these compounds inhibited the growth of BT474 and N87 at concentrations below 200nM. Structure–activity relationship studies revealed a critical role for the 5-alkynyl moieties. The representative compound 19 exhibited significant antitumor potency in a mouse xenograft model.