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J Med Chem. 2012 Sep 13;55(17):7667-85. doi: 10.1021/jm300679u. Epub 2012 Aug 29.

Discovery and in vivo evaluation of dual PI3Kβ/δ inhibitors.

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Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, USA.


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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