Discovery of AZD8154, a Dual PI3K gamma delta Inhibitor for the Treatment of Asthma

• Published in: Journal of medicinal chemistry Vol. 64; no. 12; pp. 8053 - 8075
• Main Authors: Perry, Matthew W. D., Bjorhall, Karin, Bold, Peter, Brulls, Mikael, Borjesson, Ulf, Carlsson, Johan, Chang, Hui-Fang Amy, Chen, Yunhua, Eriksson, Anders, Fihn, Britt-Marie, Fransson, Rebecca, Fredlund, Linda, Ge, Hongbin, Huang, Haijuan, Karabelas, Kostas, Bergstrom, Eva Lamm, Lever, Sarah, Lindmark, Helena, Mogemark, Mickael, Nikitidis, Antonios, Palmgren, Anna-Pia, Pemberton, Nils, Petersen, Jens, Blomqvist, Mio Rodrigo, Smith, Reed W., Thomas, Matthew J., Ullah, Victoria, Tyrchan, Christian, Wennberg, Tiiu, Eriksson, Annika Westin, Yang, Wenzhen, Zhao, Shuchun, Oster, Linda
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 24.06.2021
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; DESIGN; PI3K-DELTA; OPTIMIZATION; HIGHLY POTENT
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00434

Starting from our previously described PI3K gamma inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3K gamma delta 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.