title: Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110alpha inhibitors.
abstract: A series of 4-morpholino-2-phenylquinazolines and related derivatives were prepared and evaluated as inhibitors of PI3 kinase p110alpha. In this series, the thieno[3,2-d]pyrimidine derivative 15e showed the strongest inhibitory activity against p110alpha, with an IC(50) value of 2.0 nM, and inhibited proliferation of A375 melanoma cells with an IC(50) value of 0.58 microM. Moreover, 15e was found to be selective for p110alpha over other PI3K isoforms and protein kinases, making it the first example of a selective PI3K p110alpha inhibitor.
authors.affiliation: Institute for Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 300-2698, Japan. masahiko.hayakawa@jp.astellas.com
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hayakawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kaizawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Moritomo
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Koizumi
authors.forename: Takahide
authors.initials: T
authors.lastname: Ohishi
authors.forename: Minoru
authors.initials: M
authors.lastname: Okada
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tsukamoto
authors.forename: Peter
authors.initials: P
authors.lastname: Parker
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Mike
authors.initials: M
authors.lastname: Waterfield
mesh_terms: D000818:Animals; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one