title: Isothiazolopyrimidines and isoxazolopyrimidines as novel multi-targeted inhibitors of receptor tyrosine kinases.
abstract: A series of isothiazolopyrimidines and isoxazolopyrimidines were synthesized and identified as potent KDR inhibitors. SAR studies led to isothiazolopyrimidine urea analogs that potently inhibit VEGFR tyrosine kinases (KDR enzymatic and cellular IC(50) values below 10 nM) as well as cKIT and TIE2. The selected compounds 8 and 13 display 56% and 48% oral bioavailability in mice, respectively.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6100, USA. zhiqin.ji@abbott.com
authors.forename: Zhiqin
authors.initials: Z
authors.lastname: Ji
authors.forename: Asma A
authors.initials: AA
authors.lastname: Ahmed
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Albert
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Bouska
authors.forename: Peter F
authors.initials: PF
authors.lastname: Bousquet
authors.forename: George A
authors.initials: GA
authors.lastname: Cunha
authors.forename: Keith B
authors.initials: KB
authors.lastname: Glaser
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.forename: Junling
authors.initials: J
authors.lastname: Li
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Marcotte
authors.forename: Maria D
authors.initials: MD
authors.lastname: Moskey
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Pease
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.forename: Melinda
authors.initials: M
authors.lastname: Yates
authors.forename: Steven K
authors.initials: SK
authors.lastname: Davidsen
authors.forename: Michael R
authors.initials: MR
authors.lastname: Michaelides
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D042787:Receptor, TIE-2 / Q000378:metabolism; D013329:Structure-Activity Relationship; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; D040281:Vascular Endothelial Growth Factor Receptor-1