The optimization of aminooxadiazoles as orally active inhibitors of Cdc7

PE Harrington, MP Bourbeau, C Fotsch, M Frohn…

Index: Harrington, Paul E.; Bourbeau, Matthew P.; Fotsch, Christopher; Frohn, Michael; Pickrell, Alexander J.; Reichelt, Andreas; Sham, Kelvin; Siegmund, Aaron C.; Bailis, Julie M.; Bush, Tammy; Escobar, Sonia; Hickman, Dean; Heller, Scott; Hsieh, Faye; Orf, Jessica N.; Rong, Minqing; San Miguel, Tisha; Tan, Helming; Zalameda, Leeanne; Allen, John G. Bioorganic and Medicinal Chemistry Letters, 2013 , vol. 23, # 23 p. 6396 - 6400

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Citation Number: 5

Abstract

Abstract A series of aminooxadiazoles was optimized for inhibition of Cdc7. Early lead isoquinoline 1 suffered from modest cell potency (cellular IC 50= 0.71 μM 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 IC 50= 1.1 nM, pMCM2 IC 50= 32 nM) that demonstrated robust lowering of pMCM2 in a mouse ...