title: Tyrosine kinase inhibitors. 7. 7-Amino-4-(phenylamino)- and 7-amino-4-[(phenylmethyl)amino]pyrido[4,3-d]pyrimidines: a new class of inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor.
abstract: The synthesis of 7-aminopyrido[4,3-d]pyrimidines bearing aromatic side chains at the 4-position is reported. These compounds are shown to be a new class of inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Structure-activity relationships (SARs) for substitution in both 4-(phenylamino)- and 4-[(phenylmethyl)amino] side chains were determined, using a series of substituents (NO2, Br, CF3, OMe, NH2, and NMe2) selected primarily for their wide range of electronic properties. In the phenylamino series, 3-substituted derivatives were more potent than the corresponding 2- and 4-substituted analogues. For the 3-substituted compounds, activity was favored by electron withdrawal, in a relationship which could be quantified, with the 3-Br being the most potent compound (IC50 = 0.01 microM compared with IC50 = 0.34 microM for the unsubstituted side chain derivative). No such correlation was apparent for the 2- or 4-substituent, although Br was still the best substituent. In contrast, in the 4-[(phenylmethyl)amino] series, substitution of the side chain was not beneficial. For the 4-(phenylamino) series, the substituent SARs are broadly similar to that found previously for 4-(phenylamino)quinazolines. These results suggest that side chain SARs may be broadly invariant over a range of different chromophores, with the side chain of choice for optimization of EGFR inhibitory activity being 4-[(3-bromophenyl)amino].
authors.affiliation: Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
authors.forename: A M
authors.initials: AM
authors.lastname: Thompson
authors.forename: A J
authors.initials: AJ
authors.lastname: Bridges
authors.forename: D W
authors.initials: DW
authors.lastname: Fry
authors.forename: A J
authors.initials: AJ
authors.lastname: Kraker
authors.forename: W A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D002294:Carcinoma, Squamous Cell; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D010446:Peptide Fragments / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D010446:Peptide Fragments; D011743:Pyrimidines; D066246:ErbB Receptors; D010738:Type C Phospholipases