Discovery of triazole aminopyrazines as a highly potent and selective series of PI3Kδ inhibitors. Issue 3 (1st February 2017)

• Record Type: Journal Article
• Authors: Terstiege, Ina; Perry, Matthew; Petersen, Jens; Tyrchan, Christian; Svensson, Tor; Lindmark, Helena; Öster, Linda
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 3(2017)
• Page Start: 679
• Page End: 687
• Publication Date: 2017-02-01
• Subjects: Phosphoinositide 3-kinase -- PI3Kδ inhibitor -- Aminopyrazine -- Inflammation; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.11.004
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A novel class of potent PI3Kδ inhibitors with >1000-fold selectivity against other class I PI3K isoforms is described. Optimization of the substituents on a triazole aminopyrazine scaffold, emerging from an in-house PI3Kα program, turned moderately selective PI3Kδ compounds into highly potent and selective PI3Kδ inhibitors. These efforts resulted in a series of aminopyrazines with PI3Kδ IC50 ⩽ 1 nM in the enzyme assay, some of the most selective PI3Kδ inhibitors published to date, with a cell potency in a JeKo-cell assay of 20–120 nM.