title: 4-Anilino-6,7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermal growth factor receptor kinase and their bioisosteric relationship to the 4-anilino-6,7-dialkoxyquinazoline inhibitors.
abstract: The synthesis and SAR of a series of 4-anilino-6, 7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermal growth factor receptor (EGF-R) kinase are described. Condensation of 3, 4-dialkoxyanilines with ethyl (ethoxymethylene)cyanoacetate followed by thermal cyclization gave, regiospecifically, 6,7-dialkoxy-4-oxo-1, 4-dihydroquinoline-3-carbonitriles. Chlorination (POCl(3)) followed by the reaction with substituted anilines furnished the 4-anilino-6, 7-dialkoxyquinoline-3-carbonitrile inhibitors of EGF-R kinase. An alternate synthesis of these compounds starts with a methyl 3, 4-dialkoxybenzoate. Nitration followed by reduction (Fe, NH(4)Cl, MeOH-H(2)O) gave a methyl 2-amino-4,5-dialkoxybenzoate. Amidine formation using DMF-acetal followed by cyclization using LiCH(2)CN furnished a 6,7-dialkoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile, which was transformed as before. Compounds containing acid, ester, amide, carbinol, and aldehyde groups at the 3-position of the quinoline ring were also prepared for comparison, as were several 1-anilino-6,7-dimethoxyisoquinoline-4-carbonitriles. The compounds were evaluated for their ability to inhibit the autophosphorylation of the catalytic domain of EGF-R. The SAR of these inhibitors with respect to the nature of the 6,7-alkoxy groups, the aniline substituents, and the substituent at the 3-position was studied. The compounds were further evaluated for their ability to inhibit the growth of cell lines that overexpress EGF-R or HER-2. It was found that 4-anilinoquinoline-3-carbonitriles are effective inhibitors of EGF-R kinase with activity comparable to the 4-anilinoquinazoline-based inhibitors. A new homology model of EGF-R kinase was constructed based on the X-ray structures of Hck and FGF receptor-1 kinase. The model suggests that with the quinazoline-based inhibitors, the N3 atom is hydrogen-bonded to a water molecule which, in turn, interacts with Thr 830. It is proposed that the quinoline-3-carbonitriles bind in a similar manner where the water molecule is displaced by the cyano group which interacts with the same Thr residue.
authors.affiliation: Wyeth-Ayerst Research, A Division of American Home Products, 401 North Middletown Road, Pearl River, New York 10965-1215, USA.
authors.forename: A
authors.initials: A
authors.lastname: Wissner
authors.forename: D M
authors.initials: DM
authors.lastname: Berger
authors.forename: D H
authors.initials: DH
authors.lastname: Boschelli
authors.forename: M B
authors.initials: MB
authors.lastname: Floyd
authors.forename: L M
authors.initials: LM
authors.lastname: Greenberger
authors.forename: B C
authors.initials: BC
authors.lastname: Gruber
authors.forename: B D
authors.initials: BD
authors.lastname: Johnson
authors.forename: N
authors.initials: N
authors.lastname: Mamuya
authors.forename: R
authors.initials: R
authors.lastname: Nilakantan
authors.forename: M F
authors.initials: MF
authors.lastname: Reich
authors.forename: R
authors.initials: R
authors.lastname: Shen
authors.forename: H R
authors.initials: HR
authors.lastname: Tsou
authors.forename: E
authors.initials: E
authors.lastname: Upeslacis
authors.forename: Y F
authors.initials: YF
authors.lastname: Wang
authors.forename: B
authors.initials: B
authors.lastname: Wu
authors.forename: F
authors.initials: F
authors.lastname: Ye
authors.forename: N
authors.initials: N
authors.lastname: Zhang
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005470:Fluorometry; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009570:Nitriles; D011799:Quinazolines; D011804:Quinolines; D066246:ErbB Receptors