Identification and optimisation of a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids as potent histone deacetylase (HDAC) inhibitors

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• 作者：Steve Price ; Walter Bordogna ; Richard J. Bull ; David E. Clark ; Peter H. Crackett ; Hazel J. Dyke ; Matthew Gill ; Neil V. Harris ; Julia Gorski ; Julia Lloyd ; et al.
• 关键词：Histone deacetylase inhibitors ; HDAC ; Hydroxamic acids
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2007
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 January 2007
• 卷：17
• 期：2
• 页码：370-375
• 文件大小：168 K

摘要

Optimisation of ADS100380, a sub-micromolar HDAC inhibitor identified using a virtual screening approach, led to a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids (6a–i), that possessed significant HDAC inhibitory activity. Subsequent functionalisation of the pendent phenyl group of compounds 6f and 6g provided analogues 6j–w with further enhanced enzyme and anti-proliferative activity. Compound 6j demonstrated efficacy in a mouse xenograft experiment.