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Smaill, Jeff B; Palmer, Brian D; Rewcastle, Gordon W; Denny, William A; McNamara, Dennis J; Dobrusin, Ellen M; Bridges, Alexander J; Zhou, Hairong; Showalter, H. D. Hollis; Winters, R. Thomas; Leopold, Wilbur R; Fry, David W; Nelson, James M; Slintak, Veronika; Elliot, William L; Roberts, Billy J; Vincent, Patrick W; Patmore, Sandra J
Journal of medicinal chemistry, 05/1999, Volume: 42, Issue: 10Journal Article
A series of 6- and 7-acrylamide derivatives of the 4-(phenylamino)quinazoline and -pyridopyrimidine classes of epidermal growth factor receptor (EGFR) inhibitors were prepared from the corresponding amino compounds by reaction with either acryloyl chloride/base or acrylic acid/1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. All of the 6-acrylamides, but only the parent quinazoline 7-acrylamide, were irreversible inhibitors of the isolated enzyme, confirming that the former are better-positioned, when bound to the enzyme, to react with the critical cysteine-773. Quinazoline, pyrido3,4-dpyrimidine, and pyrido3,2-dpyrimidine 6-acrylamides were all irreversible inhibitors and showed similar high potencies in the enzyme assay (likely due to titration of the available enzyme). However the pyrido3,2-dpyrimidine analogues were 2−6-fold less potent than the others in a cellular autophosphorylation assay for EGFR in A431 cells. The quinazolines were generally less potent overall toward inhibition of heregulin-stimulated autophosphorylation of erbB2 (in MDA-MB-453-cells), whereas the pyridopyrimidines were equipotent. Selected compounds were evaluated in A431 epidermoid and H125 non-small-cell lung cancer human tumor xenografts. The compounds showed better activity when given orally than intraperitoneally. All showed significant tumor growth inhibition (stasis) over a dose range. The poor aqueous solubility of the compounds was a drawback, requiring formulation as fine particulate emulsions.
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