Tyrosine Kinase Inhibitors. 18. 6-Substituted 4-Anilinoquinazolines and 4-Anilinopyrido[3,4-d]pyrimidines as Soluble, Irreversible Inhibitors of the Epidermal Growth Factor Receptor

Abstract

4-Anilinoquinazoline- and 4-anilinopyrido[3,4-d]pyrimidine-6-acrylamides are potent pan-erbB tyrosine kinase inactivators, and one example (CI-1033) is in clinical trial. A series of analogues with a variety of Michael acceptor units at the 6-position were prepared to define the structural requirements for irreversible inhibition. A particular goal was to determine whether additional functions to increase solubility could be appended to the Michael acceptor. Substituted acrylamides were prepared by direct acylation of the corresponding 6-amines with the requisite acid or acid chloride. Vinylsulfonamide derivatives were obtained by acylation of the amines with chloroethylsulfonyl chloride followed by base-promoted elimination. Vinylsulfone and vinylsulfine derivatives were prepared by oxidation and base elimination of a hydroxyethylthio intermediate. The compounds were evaluated for their inhibition of phosphorylation of the isolated EGFR enzyme and for inhibition of EGF-stimulated autophosphorylation of EGFR in A431 cells and of heregulin-stimulated autophosphorylation of erbB2 in MDA-MB 453 cells. Substitution at the nitrogen of the acrylamide was tolerated only with a methyl group; larger substituents were dystherapeutic, and no substitution at all was tolerated at the acrylamide alpha-carbon. In contrast, while electron-donating groups at the acrylamide beta-carbon were not useful, even quite large electron-withdrawing groups (which increase its electrophilicity) were tolerated. A series of derivatives with solubility-enhancing substituents linked to the acrylamide beta-carbon via amides were potent irreversible inhibitors of isolated EGFR (IC50s = 0.4-1.1 nM), with weakly basic morpholine and imidazole derivatives being the best. Vinylsulfonamides were also potent and irreversible inhibitors, but vinylsulfones and vinylsulfines were reversible and only poorly active. Two compounds were evaluated against A431, H125, and MCF-7 xenografts in nude mice but were inferior in these assays to the clinical trial compound CI-1033.

Molecular Imaging of EGFR Kinase Activity in Tumors with 124I-Labeled Small Molecular Tracer and Positron Emission Tomography

“…Our initial selection of pharmacokinetically optimized (more hydrophilic) side-chain IPQA derivatives and their in silico SAR modeling with the activated EGFR kinase was based on previous reports [29Y31], which demonstrated that derivatization from the 6-and 7-positions of the quinazoline moiety for the compounds proposed in the current application does not inhibit their irreversible binding and inhibition of EGFR kinase. Specifically, the highly potent and irreversible inhibition of EGFR kinase activity has previously been demonstrated for the 6-acrylamido-4-(3-bromo-anilino)-7-(3-morpholin-1-yl-propyl)quinazolin, 6-acrylamido-4-(3-bromo-anilino)-7-(2-morpholin-1-ylethoxy) quinazolin [30,31], and (E)-But-2-enedioic acid [4-(3-halogeno-anilino)-quinazolin-6-yl]-amide-(3-morpholin-4-yl-propyl)-amide [29]. Moreover, in molecular structures of Iressa (AstraZeneca) and Tarceva (OSI Pharmaceuticals), both the 6-and 7-positions of the quinazolin moiety are derivatized with side chains as well.…”

New Chemical Scaffolds for Human African Trypanosomiasis Lead Discovery from a Screen of Tyrosine Kinase Inhibitor Drugs

“…The drugs were administered either orally or intraperitoneally using doses employed in murine models of proliferative disease (25,30,(43)(44)(45)) (see Materials and Methods).…”

“…4). The reason for this large difference in the performances of the two drugs might lie in the different pharmacokinetics and distribution of the drugs in mice, which is most likely influenced by the chemical substituents on the common 4-anilinoquinazoline scaffold of the drugs (20,30) (Fig. 1A).…”

QSAR studies of some anilinoquinolines for their antitumor activity as EGFR inhibitors

“…The EGFR is expressed or highly expressed in a variety of human tumors including non-small cell lung cancer (NSCLC), breast, head and neck, gastric, colorectal, esophageal, prostate, bladder, renal, pancreatic, and ovarian cancers [8]. Particularly, a large number of compounds have been synthesized and evaluated as EGFR inhibitors, with special attention being paid to compounds having a phenyl amino pyrimidine moiety in their structures [9][10][11][12][13]. Evidently Anilinoquinolines are well known EGFR inhibitors as demonstrated in various studies [14][15][16].…”