Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase 未 for the Treatment of Respiratory Disease
详细信息 查看全文
- 作者：Kenneth Down ; Augustin Amour ; Ian R. Baldwin ; Anthony W. J. Cooper ; Angela M. Deakin ; Leigh M. Felton ; Stephen B. Guntrip ; Charlotte Hardy ; Zo毛 A. Harrison ; Katherine L. Jones ; Paul Jones ; Suzanne E. Keeling ; Joelle Le ; Stefano Livia ; Fiona Lucas ; Christopher J. Lunniss ; Nigel J. Parr ; Ed Robinson ; Paul Rowland ; Sarah Smith ; Daniel A. Thomas ; Giovanni Vitulli ; Yoshiaki Washio ; J. Nicole Hamblin
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：September 24, 2015
- 年：2015
- 卷：58
- 期：18
- 页码：7381-7399
- 全文大小：1014K
- ISSN：1520-4804
文摘
Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3K未 potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3K未 over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.