Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus

McGuigan, Christopher ORCID: https://orcid.org/0000-0001-8409-710X, Madela, Karolina, Aljarah, Mohamed, Gilles, Arnaud, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, Zonta, Nicola, Chamberlain, Stanley, Vernachio, John, Hutchins, Jeff and Hall, Andrea 2010. Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus. Biorganic and Medicinal Chemistry Letters 20 (16) , pp. 4850-4854. 10.1016/j.bmcl.2010.06.094

Full text not available from this repository.

Abstract

We herein report a novel double pro-drug approach applied to the anti-HCV agent 2′-β-C-methyl guanosine. A phosphoramidate ProTide motif and a 6-O-methoxy base pro-drug moiety are combined to generate lipophilic prodrugs of the monophosphate of the guanine nucleoside. Modification of the ester and amino acid moieties lead to a compound INX-08189 that exhibits 10 nM potency in the HCV genotype 1b subgenomic replicon, thus being 500 times more potent than the parent nucleoside. The potency of the lead compound INX-08189 was shown to be consistent with intracellular 2′-C-methyl guanosine triphosphate levels in primary human hepatocytes. The separated diastereomers of INX-08189 were shown to have similar activity in the replicon assay and were also shown to be similar substrates for enzyme processing. INX-08189 has completed investigational new drug enabling studies and has been progressed into human clinical trials for the treatment of chronic HCV infection.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords:	HCV; ProTide; Phosphoramidate; Nucleoside; Nucleotide; Antiviral pro-drug; Polymerase; NS5B HCV; ProTide; Phosphoramidate; Nucleoside; Nucleotide; Antiviral pro-drug; Polymerase; NS5B
Publisher:	Elsevier
ISSN:	0960-894X
Last Modified:	05 Jan 2024 05:57
URI:	https://orca.cardiff.ac.uk/id/eprint/6965

Citation Data

Cited 85 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item