title: Discovery of imidazole vinyl pyrimidines as a novel class of kinase inhibitors which inhibit Tie-2 and are orally bioavailable.
abstract: Tie-2 is a receptor tyrosine kinase which is involved in angiogenesis and thereby growth of human tumours. The discovery and SAR of a novel class of imidazole-vinyl-pyrimidine kinase inhibitors, which inhibit Tie-2 in vitro is reported. Their synthesis was carried out by condensation of imidazole aldehydes with methyl pyrimidines. These compounds are lead-like, with low molecular weight, good physical properties and oral bioavailability.
authors.affiliation: Cancer and Infection Research Area, Mereside, Alderley Park, AstraZeneca, Macclesfield SK10 4TG, UK.
authors.forename: David
authors.initials: D
authors.lastname: Buttar
authors.forename: Mike
authors.initials: M
authors.lastname: Edge
authors.forename: Steve C
authors.initials: SC
authors.lastname: Emery
authors.forename: Martina
authors.initials: M
authors.lastname: Fitzek
authors.forename: Cheryl
authors.initials: C
authors.lastname: Forder
authors.forename: Alison
authors.initials: A
authors.lastname: Griffen
authors.forename: Barry
authors.initials: B
authors.lastname: Hayter
authors.forename: Chris F
authors.initials: CF
authors.lastname: Hayward
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Hopcroft
authors.forename: Richard W A
authors.initials: RW
authors.lastname: Luke
authors.forename: Ken
authors.initials: K
authors.lastname: Page
authors.forename: John
authors.initials: J
authors.lastname: Stawpert
authors.forename: Andy
authors.initials: A
authors.lastname: Wright
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000138:chemical synthesis*; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D009389:Neovascularization, Pathologic; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D042787:Receptor, TIE-2; C030986:pyrimidine