The imidazo[1,2-a]pyridine ring system as a scaffold for potent dual phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors.

Abstract Based on lead compound 1 , which was discovered from a high-throughput screen, a series of PI3Kα/mTOR inhibitors were evaluated that contained an imidazo[1,2- a ]pyridine as a core replacement for the benzimidazole contained in 1 . By exploring various ring systems that occupy the affinity pocket, two fragments containing a methoxypyridine were identified that gave 18 was chosen for in vivo pharmacodynamic evaluation based on its potency in the PI3Kα cellular assay, microsomal stability, and in vivo pharmacokinetic properties. In a mouse liver pharmacodynamic assay, compound 18 showed 56% inhibition of HFG-induced AKT (Ser473) phosphorylation at a 30 mg/kg dose.