학술논문
Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma
Document Type
Article
Author
Perry, Matthew W. D.; Björhall, Karin; Bold, Peter; Brűlls, Mikael; Börjesson, Ulf; Carlsson, Johan; Chang, Hui-Fang Amy; Chen, Yunhua; Eriksson, Anders; Fihn, Britt-Marie; Fransson, Rebecca; Fredlund, Linda; Ge, Hongbin; Huang, Haijuan; Karabelas, Kostas; Lamm Bergström, Eva; Lever, Sarah; Lindmark, Helena; Mogemark, Mickael; Nikitidis, Antonios; Palmgren, Anna-Pia; Pemberton, Nils; Petersen, Jens; Rodrigo Blomqvist, Mio; Smith, Reed W.; Thomas, Matthew J.; Ullah, Victoria; Tyrchan, Christian; Wennberg, Tiiu; Westin Eriksson, Annika; Yang, Wenzhen; Zhao, Shuchun; Öster, Linda
Source
Journal of Medicinal Chemistry; June 2021, Vol. 64 Issue: 12 p8053-8075, 23p
Subject
Language
ISSN
00222623; 15204804
Abstract
Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure–activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.