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

摘要: Based on lead compound 1, which was discovered from a high-throughput screen, series of PI3Kα/mTOR inhibitors were evaluated that contained an imidazo[1,2-a]pyridine as core replacement for the benzimidazole in 1. By exploring various ring systems occupy affinity pocket, two fragments containing methoxypyridine identified gave <100 nM potency toward PI3Kα enzyme and cellular assays with moderate stability rat human liver microsomes. With groups selected to analogs prepared intended ribose pocket mTOR. From these analogs, tertiary alcohol 18 chosen vivo pharmacodynamic evaluation based its assay, microsomal stability, pharmacokinetic properties. In mouse showed 56% inhibition HFG-induced AKT (Ser473) phosphorylation at 30 mg/kg dose.