Discovery of novel isothiazole inhibitors of the TrkA kinase: Structure–activity relationship, computer modeling, optimization, and identification of highly potent antagonists

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• 作者：Blaise Lippa ; Joel Morris ; Matthew Corbett ; Tricia A. Kwan ; Mark C. Noe ; Sheri L. Snow ; Thomas G. Gant ; Melchiorra Mangiaracina ; Heather A. Coffey ; Barbara Foster et al.
• 关键词：TrkA ; Antagonist ; Isothiazole ; Homology model ; Synthesis
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2006
• 出版时间：1 July 2006
• 年：2006
• 卷：16
• 期：13
• 页码：3444-3448
• 全文大小：164 K

文摘

The design, synthesis, and biological evaluation of potent inhibitors of the TrkA kinase is presented. A homology model is created to aid in the enhancement of potency and selectivity of isothiazole inhibitors found during a high-throughput screen. Three different syntheses are utilized to make diverse analogs within this series. Aminoheterocycles are found to be good urea surrogates, whereas bicyclic substituents on the C3 thio group were found to be extremely potent TrkA inhibitors in kinase and cell assays.