Wissner Allan, Overbeek Elsebe, Reich Marvin F, Floyd M Brawner, Johnson Bernard D, Mamuya Nellie, Rosfjord Edward C, Discafani Carolyn, Davis Rachel, Shi Xiaoqing, Rabindran Sridhar K, Gruber Brian C, Ye Fei, Hallett William A, Nilakantan Ramaswamy, Shen Ru, Wang Yu-Fen, Greenberger Lee M, Tsou Hwei-Ru
Chemical Sciences, Oncology and Immunoinflammatory Research, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA.
J Med Chem. 2003 Jan 2;46(1):49-63. doi: 10.1021/jm020241c.
A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.
已制备出一系列6,7-二取代-4-苯胺基喹啉-3-腈衍生物,它们作为表皮生长因子受体(EGFR)和人表皮生长因子受体2(HER-2)激酶的不可逆抑制剂发挥作用。这些抑制剂在6位含有带有水溶性取代基的丁炔酰胺、巴豆酰胺和甲基丙烯酰胺迈克尔受体。这些化合物是通过6-氨基-4-(芳基氨基)喹啉-3-腈与不饱和酰氯或混合酸酐的酰化反应制备的。我们进行了竞争反应性研究,结果表明,由于迈克尔加成的分子内催化作用,在迈克尔受体末端连接二烷基氨基会导致化合物具有更高的反应性。这与改善的水溶性一起,使得化合物具有增强的生物学特性。我们给出了与所提出的抑制机制一致的分子模拟结果。一种表现出优异口服体内活性的化合物5(EKB-569)被选作进一步研究对象,目前正处于治疗癌症的I期临床试验阶段。