227311-98-0Relevant articles and documents
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
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.
, p. 1803 - 1815 (1999)
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, pyrido[3,4-d]pyrimidine, and pyrido[3,2-d]pyrimidine 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 pyrido[3,2-d]pyrimidine 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.
PRODRUG FORMS OF KINASE INHIBITORS AND THEIR USE IN THERAPY
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Page/Page column 76, (2010/10/03)
The invention provides novel prodrug compounds comprising a kinase inhibitor and a reductively-activated fragmenting aromatic nitroheterocycle or aromatic nitrocarbocycle trigger, where the compound carries a positive charge. In preferred embodiments, the compounds are of Formula I: where: X is any negatively charged counterion; R1 is a group of the formula —(CH2)nTr, where Tr is an aromatic nitroheterocycle or aromatic nitrocarbocycle and —(CH2)nTr acts as a reductively-activated fragmenting trigger; and n is an integer from 0 to 6; R2, R3 and R4 may each independently be selected from aliphatic or aromatic groups of a tertiary amine kinase inhibitor (R2)(R3)(R4)N, or two of R2, R3, and R4 may form an aliphatic or aromatic heterocyclic amine ring of a kinase inhibitor, or one of R2, R3 and R4 may be absent and two of R2, R3 and R4 form an aromatic heterocyclic amine ring of a kinase inhibitor. The compounds of the invention are useful in treating proliferative diseases such as cancer.
