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

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 relatio...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (1), p.456-460
Hauptverfasser:	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:	Artikel
Sprache:	eng
Schlagworte:	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
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Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.10.103