Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains

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• 作者：Alexander M. Taylor ; Rishi G. Vaswani ; Victor S. Gehling ; Michael C. Hewitt ; Yves Leblanc ; James E. Audia ; Steve Bellon ; Richard T. Cummings ; Alexandre C?té ; Jean-Christophe Harmange ; Hari Jayaram ; Shivangi Joshi ; Jose M. Lora ; Jennifer A. Mertz ; Adrianne Neiss ; Eneida Pardo ; Christopher G. Nasveschuk ; Florence Poy ; Peter Sandy ; Jeremy W. Setser ; Robert J. Sims III ; Yong Tang ; Brian K. Albrecht
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：February 11, 2016
• 年：2016
• 卷：7
• 期：2
• 页码：145-150
• 全文大小：449K
• ISSN：1948-5875

文摘

Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and inflammatory disease, respectively. Herein we report substituted benzo[b]isoxazolo[4,5-d]azepines and benzotriazolo[4,3-d][1,4]diazepines as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds from these series were potent and selective in cells, and subsequent optimization of microsomal stability yielded representatives that demonstrated dose- and time-dependent reduction of plasma IL-6 in mice.