Phosphoinositide 3-kinases (PI3Ks) are lipid kinases that play a key role in the control of a wide number of cellular functions including metabolism, cell growth and motility. Class IA PI3Ks are comprised of PI3Ka, � and d and the sole representative of class IB PI3K is PI3K?. In terms of tissue distribution, PI3Ka and � are ubiquitously expressed whereas PI3K? and d are mainly expressed in leukocytes. This expression pattern, in conjunction with mouse genetic studies has established these enzymes as promising targets for the treatment of a number of inflammatory and oncologic diseases. To evaluate the in vivo impact of inhibiting both PI3K� and d isoforms a series of novel small molecule inhibitors of these two enzymes was identified. The optimized pyrrolo pyridine analog 17  was a potent and selective PI3K�/d dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analog 17  was found to be efficacious in animal models of inflammation such as a keyhole limpet hemocyanin (KLH) study and in a collagen-induced arthritis (CIA) disease model in rats. These studies highlight the potential therapeutic value of inhibiting both the PI3K� and d isoforms in the treatment of a number of inflammatory diseases.

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

244th National Meeting (2012)

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