title: Tyrosine kinase inhibitors. 16. 6,5,6-tricyclic benzothieno[3, 2-d]pyrimidines and pyrimido[5,4-b-] and -[4,5-b]ĭndoles as potent inhibitors of the epidermal growth factor receptor tyrosine kinase.
abstract: Several elaborations of the fundamental anilinopyrimidine pharmacophore have been reported as potent and selective inhibitors of the epidermal growth factor receptor (EGFr) tyrosine kinase. This paper reports on a series of inhibitors whereby some 6,5-bicyclic heteroaromatic systems were fused through their C-2 and C-3 positions to this anilinopyrimidine pharmacophore. Although the resulting tricycles did not produce the enormous potency of some of the (5/6),6,6-bicyclic systems, the best of them had IC(50)s for the EGFr TK around 1 nM. Investigation of 4-position side chains in the indolopyrimidines confirmed that m-bromoaniline was an optimal substituent for potency. Investigation of substitution within the C-(benzo)ring of benzothienopyrimidines confirmed that introduction of an extra ring can change sharply the effects of substituents when compared to similar bicyclic nuclei, and only two substituents were found which even moderately enhanced inhibitory activity over the parent compound for this series.
authors.affiliation: Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. hollis.showalter@wl.com
authors.forename: H D
authors.initials: HD
authors.lastname: Showalter
authors.forename: A J
authors.initials: AJ
authors.lastname: Bridges
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.forename: A D
authors.initials: AD
authors.lastname: Sercel
authors.forename: A
authors.initials: A
authors.lastname: McMichael
authors.forename: D W
authors.initials: DW
authors.lastname: Fry
mesh_terms: D000595:Amino Acid Sequence; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D011743:Pyrimidines; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases