Discovery and in Vivo Evaluation of Dual PI3Kβ/δ Inhibitors
Felix González-López de Turiso(Amgen (United States)), Youngsook Shin, Matthew F. Brown, Mario Cardozo, Yi Chen, David Fong(Amgen (United States)), Xiaolin Hao, Xiaodong He, Kirk R. Henne, Yiling Hu(Amgen (United States)), Michael G. Johnson, Todd J. Kohn, Julia Lohman, Helen J. McBride(Amgen (United States)), Lawrence R. McGee, Julio C. Medina, Daniela Metz(Amgen (United States)), Kent Miner(Amgen (United States)), Deanna Mohn(Amgen (United States)), Vatee Pattaropong, Jennifer L. Seganish, Jillian Simard, Sharon Wannberg(Amgen (United States)), Douglas A. Whittington(Amgen (United States)), Gang Yu(Amgen (United States)), Timothy D. Cushing
Cited by 50Open Access
Abstract
Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kβ/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kβ and δ isoforms in the treatment of a number of inflammatory diseases.
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