beta-D-2 '-C-Methyl-2,6-diaminopurine Ribonucleoside Phosphoramidates are Potent and Selective Inhibitors of Hepatitis C Virus (HCV) and Are Bioconverted Intracellularly to Bioactive 2,6-Diaminopurine and Guanosine 5 '-Triphosphate Forms

• Type of Material: Article
• Authors: Longhu Zhou, Emory University; HongWang Zhang, Emory University; Sijia Tao, Emory University; Leda Bassit, Emory University; Tony Whitaker, CoCrystal Pharma, Inc.; Tamara R. McBrayer, Veterans Affairs Medical Center; Maryam Ehteshami, Emory University; Sheida Amiralaei, Emory University; Ugo Pradere, Emory University; Jong Cho, Emory University; Franck Amblard, Emory University; Drew Bobeck, CoCrystal Pharma, Inc.; Mervi Detorio, Emory University; Steven Coats, Emory University; Raymond Schinazi, Emory University
• Language: English
• Date: 2015-04-23
• Publisher: AMER CHEMICAL SOC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2015
• Final Published Version (URL): http://dx.doi.org/10.1021/jm501874e
• Title of Journal or Parent Work: JOURNAL OF MEDICINAL CHEMISTRY
• Volume: 58
• Issue: 8
• Start Page: 3445
• End Page: 3458
• Grant/Funding Information: This work was supported in part by NIH CFAR Grant 2P30AI050409 and by the Department of Veterans Affairs.; R.F.S. is the Chairman and a major shareholder of CoCrystal Pharma, Inc.
• Keywords: DRUGS; Pharmacology & Pharmacy; Chemistry, Medicinal; Science & Technology; INTERIM ANALYSIS; Life Sciences & Biomedicine; PRODRUGS; ACTING ANTIVIRAL AGENTS; ARYL PHOSPHATE DERIVATIVES; INFECTION; ACTIVATION; ANTI-HCV; BETA-D-2'-DEOXY-2'-FLUORO-2'-C-METHYLCYTIDINE; VIRAL-HEPATITIS
• Research Categories: Health Sciences, Pharmacology; Chemistry, General

Abstract

The conversion of selected β-d-2,6-diaminopurine nucleosides (DAPNs) to their phosphoramidate prodrug (PD) substantially blocks the conversion to the G-analog allowing for the generation of two bioactive nucleoside triphosphates (NTPs) in human hepatocytes. A variety of 2′-C-methyl DAPN-PDs were prepared and evaluated for inhibition of HCV viral replication in Huh-7 cells, cytotoxicity in various cell lines, and cellular pharmacology in both Huh-7 and primary human liver cells. The DAPN-PDs were pan-genotypic, effective against various HCV resistant mutants, and resistant variants could not be selected. 2′-C-Me-DAPN-TP and 2′-C-Me-GTP were chain terminators for genotype 1b HCV-pol, and single nucleotide incorporation assays revealed that 2′-C-Me-DAPN-TP was incorporated opposite U. No cytotoxicity was observed with our DAPN-PD when tested up to 50 μM. A novel, DAPN-PD, 15c, has been selected for further evaluation because of its good virologic and toxicologic profile and its ability to deliver two active metabolites, potentially simplifying HCV treatment.