INHIBITORS OF THE EPIDERMAL GROWTH-FACTOR RECEPTOR PROTEIN-TYROSINE KINASE - A QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS

Hansch and Free-Wilson analyses are described on a data set, 4-anilino quinazolines [the analogues of 3-(3-bromo-anilino)-6,7-dimethoxy quina zoline: PD 153035], as inhibitors of the epidermal growth factor recep tor protein tyrosine kinase. These analyses have helped to ascertain t he role of different substituents in explaining the observed inhibitor y activities. From both approaches, it is concluded that the combined electron-donating nature of R-1- and R-2-substitutions of the quinazol ine ring and the electron-withdrawing nature of the X-substitution of the anilino-ring are beneficial for increasing the inhibition activity of a compound. Further, the symmetrical alkoxy substituents present a t the R-1- and R-2-positions are also engaged in a steric interaction which was determined quantilatively through the parabolic relationship between the activity and combined molar refraction parameter, Sigma M R of the substituents.