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. Issue 4 (15th February 2017)

• Record Type: Journal Article
• Authors: Qin, Lan-Ying; Ruan, Zheming; Cherney, Robert J.; Dhar, T.G. Murali; Neels, James; Weigelt, Carolyn A.; Sack, John S.; Srivastava, Anurag S.; Cornelius, Lyndon A.M.; Tino, Joseph A.; Stefanski, Kevin; Gu, Xiaomei; Xie, Jenny; Susulic, Vojkan; Yang, Xiaoxia; Yarde-Chinn, Melissa; Skala, Stacey; Bosnius, Ruth; Goldstein, Christine; Davies, Paul; Ruepp, Stefan; Salter-Cid, Luisa; Bhide, Rajeev S.; Poss, Michael A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 4(2017)
• Page Start: 855
• Page End: 861
• Publication Date: 2017-02-15
• Subjects: PI3Kδ -- 7-Phenylpyrrolo[2, 1-f][1, 2, 4]triazin-4-amine -- Autoimmune diseases -- Rheumatoid arthritis -- Phosphoinositide 3-kinases; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.01.016
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.