title: Synthesis and biological evaluation of pyrido[3',2':4,5]furo[3,2-d]pyrimidine derivatives as novel PI3 kinase p110alpha inhibitors.
abstract: 4-Morpholin-4-ylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine 2a was discovered in our chemical library as a novel p110alpha inhibitor with an IC(50) of 1.4 microM. By structural modification of 2a, the 2-aryl-4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidine derivative 10e was discovered as a p110alpha inhibitor with approximately 400-fold greater potency than 2a. Evaluation of isoform selectivity showed that 10e is a potent inhibitor of p110beta. Furthermore, 10e showed anti-proliferative activity in various cell lines, including multi-drug resistant MCF7/ADR-res cells, and was effective against HeLa human cervical tumor xenografts in nude mice.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 5-2-3 Tokodai, 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: Mayumi
authors.initials: M
authors.lastname: Yamano
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: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Michael D
authors.initials: MD
authors.lastname: Waterfield
authors.forename: Peter
authors.initials: P
authors.lastname: Parker
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D058534:Class I Phosphatidylinositol 3-Kinases; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008968:Molecular Conformation; D009368:Neoplasm Transplantation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000138:chemical synthesis*; D011743:Pyrimidines / Q000138:chemical synthesis*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D058534:Class I Phosphatidylinositol 3-Kinases; C497132:PIK3CB protein, human