Identification of 4-Aminopyrazolylpyrimidines as Potent Inhibitors of Trk Kinases

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• 作者：Tao Wang ; Michelle L. Lamb ; David A. Scott ; Haixia Wang ; Michael H. Block ; Paul D. Lyne ; John W. Lee ; Audrey M. Davies ; Hai-Jun Zhang ; Yanyi Zhu ; Fei Gu ; Yongxin Han ; Bin Wang ; Peter J. Mohr ; Robert J
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：August 14, 2008
• 年：2008
• 卷：51
• 期：15
• 页码：4672-4684
• 全文大小：293K
• 年卷期：v.51,no.15(August 14, 2008)
• ISSN：1520-4804

文摘

The design, synthesis and biological evaluation of a series of 4-aminopyrazolylpyrimidines as potent Trk kinase inhibitors is reported. High-throughput screening identified a promising hit in the 4-aminopyrazolylpyrimidine chemotype. Initial optimization of the series led to more potent Trk inhibitors. Further optimization using two strategies resulted in significant improvement of physical properties and led to the discovery of 10z (AZ-23), a potent, orally bioavailable Trk A/B inhibitor. The compound offers the potential to test the hypothesis that modulation of Trk activity will be of benefit in the treatment of cancer and other indications in vivo.