Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin
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- 作者：Peter JonesR. Ian Storer ; Yogesh A. Sabnis ; Florian M. Wakenhut ; Gavin A. Whitlock ; Katherine S. England ; Takasuke Mukaiyama ; Christoph M. Dehnhardt ; Jotham W. Coe ; Steve W. Kortum ; Jill E. Chrencik ; David G. Brown ; Rhys M. Jones ; John R. Murphy ; Thean Yeoh ; Paul Morgan ; Iain Kilty
- 刊名：Journal of Medicinal Chemistry
- 出版年：2017
- 出版时间：January 26, 2017
- 年：2017
- 卷：60
- 期：2
- 页码：767-786
- 全文大小：1082K
- ISSN：1520-4804
文摘
By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies.