Optimization of 3-Cyano-7-cyclopropylamino-pyrazolopyrimidines Toward the Development of an In Vivo Chemical Probe for CSNK2

Abstract

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 analogs 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 co-dosing with ethacrynic acid, a covalent reversible GST inhibitor, was developed to improve the exposure of analog 2h in mice. A double co-dosing 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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/540828v2_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@1ae672borg.highwire.dtl.DTLVardef@f7777corg.highwire.dtl.DTLVardef@c5aae8org.highwire.dtl.DTLVardef@1579f2f_HPS_FORMAT_FIGEXP M_FIG C_FIG