Optimization of 3-Cyano-7-cyclopropylamino-pyrazolo[1,5-a]pyrimidines Toward the Development of an In Vivo Chemical Probe for CSNK2A.
Xuan YangHan Wee OngRebekah J DickmanderJeffery L SmithJason W BrownWilliam TaoEdcon ChangNathaniel J MoormanAlison D AxtmanTimothy M WillsonPublished in: bioRxiv : the preprint server for biology (2023)
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.
Keyphrases
- phase ii
- clinical trial
- randomized controlled trial
- high fat diet induced
- induced apoptosis
- open label
- living cells
- quantum dots
- cell cycle arrest
- type diabetes
- molecular docking
- double blind
- protein kinase
- insulin resistance
- cell death
- phase iii
- wild type
- molecular dynamics simulations
- study protocol
- cell proliferation
- placebo controlled
- climate change
- human health
- skeletal muscle