title: Tyrosine kinase inhibitors. 10. Isomeric 4-[(3-bromophenyl)amino]pyrido[d]-pyrimidines are potent ATP binding site inhibitors of the tyrosine kinase function of the epidermal growth factor receptor.
abstract: Following the discovery of the very high inhibitory ability of the 4-[(3-bromophenyl)amino]-quinazolines against the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) (e.g., 3, IC50 0.029 nM), four series of related pyrido[d]pyrimidines bearing electron-donating groups at the 6- or 7-positions have been synthesized and evaluated. The compounds were prepared by nucleophilic substitution of the corresponding 6- and 7-fluoro analogues. While members of all series showed potent inhibitory activity against isolated EGFR, there were important differences between the different isomeric pyrido[d]pyrimidines and the parent quinazolines. Overall, the [3,4-d] and [4,3-d] series were the most potent, followed by the [3,2-d] compounds, with the [2,3-d] analogues being least active. Whereas in the parent quinazoline series the addition of steric bulk to a 6- or 7-NH2 substituent (i.e., NHMe and NMe2 groups) dramatically decreased potency, no such trend was discernable in the [3,2-d] series. Furthermore, in the 7-substituted pyrido[4,3-d]- and 6-substituted pyrido[3,4-d]pyrimidine series, and to a limited extent in the 7-substituted pyrido[2,3-d] series, such substitution increased potency dramatically, to the extent that the 7-(methylamino)pyrido[4,3-d]pyrimidine (5f) (IC50 0.13 nM) and 6-(methylamino)pyrido[3,4-d]pyrimidine (7f) (IC50 0.008 nM) constitute important new leads. Selected compounds were evaluated for their ability to inhibit EGFR autophosphorylation in A431 cells, and a positive quantitative correlation was found between this activity and inhibitory activity against the isolated enzyme.
authors.affiliation: Cancer Society Research Laboratory, University of Auckland School of Medicine, New Zealand.
authors.forename: G W
authors.initials: GW
authors.lastname: Rewcastle
authors.forename: B D
authors.initials: BD
authors.lastname: Palmer
authors.forename: A M
authors.initials: AM
authors.lastname: Thompson
authors.forename: A J
authors.initials: AJ
authors.lastname: Bridges
authors.forename: D R
authors.initials: DR
authors.lastname: Cody
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.forename: D W
authors.initials: DW
authors.lastname: Fry
authors.forename: A
authors.initials: A
authors.lastname: McMichael
authors.forename: W A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D010766:Phosphorylation; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D011743:Pyrimidines; D066246:ErbB Receptors