The optimization of aminooxadiazoles as orally active inhibitors of Cdc7

详细信息    查看全文

• 作者：Paul E. Harrington ; Matthew P. Bourbeau ; Christopher Fotsch ; Michael Frohn ; Alex ; er J. Pickrell ; Andreas Reichelt ; Kelvin Sham ; Aaron C. Siegmund ; Julie M. Bailis ; Tammy Bush ; Sonia Escobar ; Dean Hickman ; Scott Heller ; Faye Hsieh ; Jessica N. Orf ; Minqing Rong ; Tisha San Miguel ; Helming Tan ; Leeanne Zalameda ; John G. Allen ; et al.
• 关键词：Cdc7 ; MCM2 ; Kinase inhibitor ; Azaindole ; Cancer
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：1 December, 2013
• 年：2013
• 卷：23
• 期：23
• 页码：6396-6400
• 全文大小：1009 K

文摘

A series of aminooxadiazoles was optimized for inhibition of Cdc7. Early lead isoquinoline 1 suffered from modest cell potency (cellular IC₅₀ = 0.71 渭M measuring pMCM2), low selectivity against structurally related kinases, and high IV clearance in rats (CL = 18 L/h/kg). Extensive optimization resulted in azaindole 26 (Cdc7 IC₅₀ = 1.1 nM, pMCM2 IC₅₀ = 32 nM) that demonstrated robust lowering of pMCM2 in a mouse pharmacodynamic (PD) model when dosed orally. Modifications to improve the pharmacokinetic profile of this series were guided by trapping experiments with glutathione in rat hepatocytes.