Optimization of 6,7-Disubstituted-4-(arylamino)quinoline-3-carbonitriles as Orally Active, Irreversible Inhibitors of Human Epidermal Growth Factor Receptor-2 Kinase Activity

作者：Hwei‐Ru Tsou, Elsebe G. Overbeek-Klumpers, William Andrew Hallett, Marvin F. Reich, M. Brawner Floyd, Bernard D. Johnson, Ronald S. Michalak, Ramaswamy Nilakantan, Carolyn M. Discafani, Jonathan Golas, Sridhar K. Rabindran, Ru Shen, Xiaoqing Shi, Yu‐Fen Wang, Janis Upeslacis, Allan Wissner · 发表于：Journal of Medicinal Chemistry · 年份：2005 · DOI：10.1021/jm040159c · 被引用次数：302 · 研究领域：HER2/EGFR in Cancer Research、Monoclonal and Polyclonal Antibodies Research、Chemical Synthesis and Analysis

A series of new 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitrile derivatives that function as irreversible inhibitors of human epidermal growth factor receptor-2 (HER-2) and epidermal growth factor receptor (EGFR) kinases have been prepared. These compounds demonstrated enhanced activities for inhibiting HER-2 kinase and the growth of HER-2 positive cells compared to our EGFR kinase inhibitor 86 (EKB-569). Three synthetic routes were used to prepare these compounds. They were prepared mostly by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or by amination of 4-chloro-6-(crotonamido)quinoline-3-carbonitriles with monocyclic or bicyclic anilines. The third route was developed to prepare a key intermediate, 6-acetamido-4-chloroquinoline-3-carbonitrile, that involved a safer cyclization step. We show that attaching a large lipophilic group at the para position of the 4-(arylamino) ring results in improved potency for inhibiting HER-2 kinase. We also show the importance of a basic dialkylamino group at the end of the Michael acceptor for activity, due to intramolecular catalysis of the Michael addition. This, along with improved water solubility, resulted in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. Binding studies of one compound, 25o (C-14 radiolabeled), showed that it binds irreversibly to HER-2 protein in BT474 cells. Furthermore...