DMPK and Metabolism Studies of Nucleoside Phosphoramidates Including INX-08189, A Novel Double Pro-drug and Clinical Candidate for Hepatitis C Virus Therapy

Abstract

Hepatitis C Virus (HCV) infection is a serious health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in an estimated 2–15% of the world's population. A collaboration between Inhibitex and the University of Caridiff in Wales has produced a novel double pro-drug approach to the anti-HCV agent 2′-β-C-methylguanosine. A phosphoramidate (ProTide) motif and a C6-methoxy base pro-drug moiety are combined to generate lipophilic prodrugs of the monophosphate of the guanine nucleoside. Extensive DMPK studies in multiple species which supported the selection of the lead compound will be discussed. Details of the pre-clinical development of INX-08189 including radiolabeled metabolism studies will be described. INX-08189 has completed investigational new drug enabling studies and has been progressed into human clinical trials for the treatment of chronic HCV infection.