Discovery of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent and selective PI3Kδ inhibitors
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- 作者：Lan-Ying Qin ; lan-ying.qin@bms.com ; Zheming Ruan ; Robert J. Cherney ; T.G. Murali Dhar ; James Neels ; Carolyn A. Weigelt ; John S. Sack ; Anurag S. Srivastava ; Lyndon A.M. Cornelius ; Joseph A. Tino ; Kevin Stefanski ; Xiaomei Gu ; Jenny Xie ; Vojkan Susulic ; Xiaoxia Yang ; Melissa Yarde-Chinn ; Stacey Skala ; Ruth Bosnius ; Christine Goldstein ; Paul Davies ; Stefan Ruepp ; Luisa Salter-Cid ; Rajeev S. Bhide ; Michael A. Poss
- 关键词：PI3Kδ ; 7-Phenylpyrrolo[2 ; 1-f][1 ; 2 ; 4]triazin-4-amine ; Autoimmune diseases ; Rheumatoid arthritis ; Phosphoinositide 3-kinases
- 刊名：Bioorganic & Medicinal Chemistry Letters
- 出版年：2017
- 出版时间：15 February 2017
- 年：2017
- 卷：27
- 期：4
- 页码：855-861
- 全文大小：4003 K
- 卷排序：27
文摘
As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.