4-Anilino-6,7-dialkoxyquinolime-3-carbonitrile inhibitors of epidermal growth factor receptor kinase and their bioisosteric relationship to the 4-anilino-6,7-dialkoxyquinazoline inhibitors

被引：198

作者：

Wissner, A ^{[1
]}

Berger, DM ^{[1
]}

Boschelli, DH ^{[1
]}

Floyd, MB ^{[1
]}

Greenberger, LM ^{[1
]}

Gruber, BC ^{[1
]}

Johnson, BD ^{[1
]}

Mamuya, N ^{[1
]}

Nilakantan, R ^{[1
]}

Reich, MF ^{[1
]}

Shen, R ^{[1
]}

Tsou, HR ^{[1
]}

Upeslacis, E ^{[1
]}

Wang, YF ^{[1
]}

Wu, BQ ^{[1
]}

Ye, F ^{[1
]}

Zhang, N ^{[1
]}

机构：

[1] Wyeth Ayerst Res, Pearl River, NY 10965 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2000年 / 43卷 / 17期

关键词：

D O I：

10.1021/jm000206a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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)cyano acetate followed by thermal cyclization gave, regiospecifically, 6,7-dialkoxy-4-oxo-1,4-dihydroquinoline-3-carbonitriles. Chlorination (POCl3) 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, NH4Cl, MeOH-H2O) gave a methyl 2-amino-4,5-dialkoxybenzoate. Amidine formation using DMF-acetal followed by cyclization using LiCH2CN 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-carbonitiriles 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-anilino quinoline-3-carbonitriles are effective inhibitors of EGF-R kinase with activity comparable to the 4-anilinoquinazoline-based inhibitors. A new homology model of EG;F-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.

引用

页码：3244 / 3256

页数：13

共 45 条

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