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

  • Bioorg Med Chem Lett. 2012 Jan 1;22(1):456-60. doi: 10.1016/j.bmcl.2011.10.103.
Naoyuki Suzuki  1 ,  Takeshi Shiota ,  Fumihiko Watanabe ,  Norihiro Haga ,  Takami Murashi ,  Takafumi Ohara ,  Kenji Matsuo ,  Naoki Omori ,  Hiroshi Yari ,  Keiji Dohi ,  Makiko Inoue ,  Motofumi Iguchi ,  Jyunko Sentou ,  Tooru Wada
Affiliations
  • 1. Shionogi Medicinal Research Laboratories, Shionogi & Co., Ltd, 12-4, Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan. [email protected]
PMID: 22101132 DOI: 10.1016/j.bmcl.2011.10.103
Abstract

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.