Discovery and SAR of pyrrolo[2, 1-f][1, 2, 4]triazin-4-amines as potent and selective PI3Kδ inhibitors. Issue 17 (1st September 2016)

• Record Type: Journal Article
• Authors: Bhide, Rajeev S.; Neels, James; Qin, Lan-Ying; Ruan, Zheming; Stachura, Sylwia; Weigelt, Carolyn; Sack, John S.; Stefanski, Kevin; Gu, Xiaomei; Xie, Jenny H.; Goldstine, Christine B.; Skala, Stacey; Pedicord, Donna L.; Ruepp, Stefan; Dhar, T.G. Murali; Carter, Percy H.; Salter-Cid, Luisa M.; Poss, Michael A.; Davies, Paul
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 17(2016)
• Page Start: 4256
• Page End: 4260
• Publication Date: 2016-09-01
• Subjects: PI3Kδ -- Pyrrolo[2, 1-f][1, 2, 4]triazin-4-amine -- Rheumatoid arthritis -- Phosphatidylinositol-3 kinases; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.07.047
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.