Optimization of 3-Cyano-7-cyclopropylamino-pyrazolo[1,5- <i>a</i> ]pyrimidines toward the Development of an In Vivo Chemical Probe for CSNK2A
Xuan Yang, Han Wee Ong, Rebekah J. Dickmander, Jeffery L. Smith, Jason W. Brown, William C. Tao, Edcon Chang, Nathaniel J. Moorman, Alison D. Axtman, Timothy M. Willson
Abstract
High Resolution Image Download MS PowerPoint Slide 3-Cyano-7-cyclopropylamino-pyrazolo[1,5- a ]pyrimidines, including the chemical probe SGC-CK2-1, are potent and selective inhibitors of CSNK2A in cells but have limited utility in animal models due to their poor pharmacokinetic properties. While developing analogues with reduced intrinsic clearance and the potential for sustained exposure in mice, we discovered that phase II conjugation by GST enzymes was a major metabolic transformation in hepatocytes. A protocol for codosing with ethacrynic acid, a covalent reversible GST inhibitor, was developed to improve the exposure of analogue 2h in mice. A double codosing protocol, using a combination of ethacrynic acid and irreversible P450 inhibitor 1-aminobenzotriazole, increased the blood level of 2h by 40-fold at a 5 h time point.