Discovery of Imidazoquinolines as a Novel Class of Potent, Selective, and in Vivo Efficacious Cancer Osaka Thyroid (COT) Kinase Inhibitors

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• 作者：Ralf Glatthar ; Aleksandar Stojanovic ; Thomas Troxler ; Henri Mattes ; Henrik Möbitz ; Rene Beerli ; Joachim Blanz ; Ernst Gassmann ; Peter Drückes ; Gabriele Fendrich ; Sascha Gutmann ; Georg Martiny-Baron ; Fiona Spence ; Jeff Hornfeld ; John Edmonson Peel ; Helmut Sparrer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：August 25, 2016
• 年：2016
• 卷：59
• 期：16
• 页码：7544-7560
• 全文大小：719K
• 年卷期：0
• ISSN：1520-4804

文摘

Cancer Osaka thyroid (COT) kinase is an important regulator of pro-inflammatory cytokines in macrophages. Thus, pharmacologic inhibition of COT should be a valid approach to therapeutically intervene in the pathogenesis of macrophage-driven inflammatory diseases such as rheumatoid arthritis. We report the discovery and chemical optimization of a novel series of COT kinase inhibitors, with unprecedented nanomolar potency for the inhibition of TNFα. Pharmacological profiling in vivo revealed a high metabolism of these compounds in rats which was demonstrated to be predominantly attributed to aldehyde oxidase. Due to the very low activity of hepatic AO in the dog, the selected candidate 32 displayed significant blood exposure in dogs which resulted in a clear prevention of inflammation-driven lameness. Taken together, the described compounds both potently and selectively inhibit COT kinase in primary human cells and ameliorate inflammatory pathologies in vivo, supporting the notion that COT is an appropriate therapeutic target for inflammatory diseases.