title: Discovery of novel 5-alkynyl-4-anilinopyrimidines as potent, orally active dual inhibitors of EGFR and Her-2 tyrosine kinases.
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.
authors.affiliation: Shionogi Medicinal Research Laboratories, Shionogi & Co., Ltd, 12-4, Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan. naoyuki.suzuki@shionogi.co.jp
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Suzuki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shiota
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Watanabe
authors.forename: Norihiro
authors.initials: N
authors.lastname: Haga
authors.forename: Takami
authors.initials: T
authors.lastname: Murashi
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ohara
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsuo
authors.forename: Naoki
authors.initials: N
authors.lastname: Omori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yari
authors.forename: Keiji
authors.initials: K
authors.lastname: Dohi
authors.forename: Makiko
authors.initials: M
authors.lastname: Inoue
authors.forename: Motofumi
authors.initials: M
authors.lastname: Iguchi
authors.forename: Jyunko
authors.initials: J
authors.lastname: Sentou
authors.forename: Tooru
authors.initials: T
authors.lastname: Wada
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D011743:Pyrimidines / Q000737:chemistry; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases