Inhibitors of the epidermal growth factor receptor protein tyrosine kinase: a quantitative structure-activity relationship analysis.

Abstract

Hansch and Free-Wilson analyses are described on a data set, 4-anilinoquinazolines [the analogues of 4-(3-bromo-anilino)-6,7-dimethoxy quinazoline: PD 153035], as inhibitors of the epidermal growth factor receptor protein tyrosine kinase. These analyses have helped to ascertain the role of different substituents in explaining the observed inhibitory activities. From both approaches, it is concluded that the combined electron-donating nature of R1- and R2-substitutions of the quinazoline 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 at the R1- and R2-positions are also engaged in a steric interaction which was determined quantitatively through the parabolic relationship between the activity and combined molar refraction parameter, sigma MR of the substituents.