Development of SGC-GAK-1 as an orally active in vivo probe for cyclin G associated kinase through cytochrome P450 inhibition

Autor: Christopher R. M. Asquith, William J. Zuercher, Julie E. Pickett, Timothy M. Willson, James M. Bennett, Carrow I. Wells, Zengbiao Li, Lianyong Su, Jonathan M. Elkins, Tuomo Laitinen
Rok vydání: 2019
Předmět:
DOI: 10.1101/629220
Popis: SGC-GAK-1 (1), a potent, selective, cell-active chemical probe for cyclin G associated kinase (GAK), was rapidly metabolized in mouse liver microsomes by P450 mediated oxidation. 1 displayed rapid clearance in mice, limiting its utility for in vivo studies. All chemical modifications of 1 that improved metabolic stability led to a loss in GAK activity. However, pretreatment of liver microsomes with the irreversible cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) decreased intrinsic clearance of 1. Coadministration of ABT also greatly improved plasma exposure of 1 in mice, supporting its use as a chemical probe to study the in vivo biology of GAK inhibition.
Databáze: OpenAIRE
načítá se...