Tyrosine kinase inhibitors. 15. 4-(Phenylamino)quinazoline and 4-(phenylamino)pyrido[d]pyrimidine acrylamides as irreversible inhibitors of the ATP binding site of the epidermal growth factor receptor.

摘要: A series of 6- and 7-acrylamide derivatives the 4-(phenylamino)quinazoline -pyridopyrimidine classes epidermal growth factor receptor (EGFR) inhibitors were prepared from corresponding amino compounds by reaction with either acryloyl chloride/base or acrylic acid/1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. All 6-acrylamides, but only parent quinazoline 7-acrylamide, irreversible isolated enzyme, confirming that former are better-positioned, when bound to react critical cysteine-773. Quinazoline, pyrido[3,4-d]pyrimidine, pyrido[3,2-d]pyrimidine 6-acrylamides all showed similar high potencies in enzyme assay (likely due titration available enzyme). However analogues 2-6-fold less potent than others a cellular autophosphorylation for EGFR A431 cells. The quinazolines generally overall toward inhibition heregulin-stimulated erbB2 (in MDA-MB-453-cells), whereas pyridopyrimidines equipotent. Selected evaluated epidermoid H125 non-small-cell lung cancer human tumor xenografts. better activity given orally intraperitoneally. significant (stasis) over dose range. poor aqueous solubility was drawback, requiring formulation as fine particulate emulsions.