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

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• 作者：Markian M. Stec^a ; ^{mstec@amgen.com" class="auth_mail" title="E-mail the corresponding author} ; Kristin L. Andrews^d ; Yunxin Bo^a ; Sean Caenepeel^b ; Hongyu Liao^a ; John McCarter^f ; Erin L. Mullady^g ; Tisha San Miguel^f ; Raju Subramanian^c ; Nuria Tamayo^a ; Douglas A. Whittington^e ; Ling Wang^b ; Tian Wu^h ; Leeanne P. Zalameda^f ; Nancy Zhang^b ; Paul E. Hughes^b ; Mark H. Norman^a
• 关键词：Phosphoinositide 3-kinase ; Imidazo[1 ; 2-a]pyridine ; Ribose pocket ; Affinity pocket ; Kinase inhibitor ; mTOR
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：1 October 2015
• 年：2015
• 卷：25
• 期：19
• 页码：4136-4142
• 全文大小：1992 K

文摘

Based on lead compound 1, which was discovered from a high-throughput screen, a series of PI3K伪/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 <100 nM potency toward PI3K伪 in enzyme and cellular assays with moderate stability in rat and human liver microsomes. With the two methoxypyridine groups selected to occupy the affinity pocket, analogs were prepared with various fragments intended to occupy the ribose pocket of PI3K伪 and mTOR. From these analogs, tertiary alcohol 18 was chosen for in vivo pharmacodynamic evaluation based on its potency in the PI3K伪 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.