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

Article abstract of DOI:10.1021/jm00019a007

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-(phenylamine)- 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 μM compared with IC₅₀ = 0.34μM 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].