Our 2’-C-Methyl ribonucleosides class includes the range shown in Table 1.
The sugar-modified ribonucleoside analogues possessing a beta-alkyl substituent at the 2’ position of the ribose moiety are potent and broad-spectrum anti-RNA virus agents.
The more specific 2’-C-Methyl ribonucleoside class (scheme 1), is a potent anti-HCV inhibitor class. Therein, Cytidine NM07918
, Adenosine NM07919
and Guanosine NM07819
derivatives inhibit the HCV NS5B polymerase and the HCV RNA replication in the whole replicon assay. Furthermore, the 2’-C-Methyl ribonucleosides class also inhibit the replication of Flaviviridae
viruses such as bovine diarrhoea, yellow fever, and West African Nile viruses.
The 2’-C-Methyl ribonucleosides have been proven to act as chain-terminating inhibitors of HCV genome replication. 2’-C-Methyl ribonucleosides are converted in cells to their corresponding 5’-triphosphates (scheme 2), which are incorporated by the viral RdRp NS5 polymerase into nascent nucleic acid chains, whereupon they prevent the incorporation of subsequent nucleotides and result in the formation of incomplete, non-functional RNA or DNA products.
Unfortunately, their potential as therapeutically useful nucleosides is often limited by poor pharmacokinetic parameters. For example, the half-life of the 2’-C-Methyladenosine has been demonstrated to be unsatisfactorily short, whereas the 2’-C-Methylguanosine has excellent oral bioavailability, but unfortunately lacks robust cell penetration and is then inefficiently converted to its active corresponding triphosphate. In that context, some modifications have been developed in order to improve the pharmacokinetic parameters.
Some interesting pro-drugs of 2’-C-branched sugar nucleosides
have been developed to overcome these limitations for HCV therapy. The first pro-drug designed on the sugar moiety of the 2’-C-Methyl ribonucleosides was developed on the 3’-position. Valopicitabine (the 3’-O
-Valinyl ester dihydrochloride salt pro-drug of the 2’-C
) has been identified has an excellent pro-drug (scheme 3). The Physicochemical, pharmacokinetic, and toxicokinetic studies have shown that Valopicitabine
is an acid-stable pro-drug of 2’-C
-methylcytidine with excellent profiles. This pro-drug is rapidly converted into the 2’-C
in both human plasma and whole blood.
Subsequently more of the currently promising pro-drugs have been developed on the 5’-position of the sugar. The liver-targeted nucleotide pro-drugs IDX-184 (pro-drug of 2'-C-Methylguanosine NM07819
) and INX-08189 (BMS986094,pro-drug of 2-Amino-6-methoxy-2'-C-Methylguanosine) have been designed to selectively deliver the 5’-monophosphate of 2’-C-Methylguanosine (2’-MeG-MP) in hepatocytes (scheme 4). By avoiding the rate-limiting mono-phosphorylation process, 2’-MeG-MP can be efficiently converted to its active 5’-triphosphate within hepatocytes by cellular kinases.
Secondary modifications, in particular on the hetero-base moiety have also proven to have a positive effect on the pharmacokinetic parameters while maintaining their robust HCV-activity. The 7-deaza modification of several purine nucleosides is typically a good example of this approach.
This modification of the 2'-C-Methyladenosine MK-0608 (7-Deaza-2'-C-methyladenosine ND08351
) improves the pharmacokinetic properties in animal models, of HCV-infected chimpanzees
and is a potent inhibitor of HCV replication with low cellular toxicity (scheme 5).
It also acts as a chain-terminating inhibitor of HCV genome replication, but it should be noted that this activity is due to the 2’-C-methyl substituent and not the 7-deaza modifications.
The synthesis of 2’-C-Methyl ribonucleosides has been well described since the 1960’s, beginning first from halides of 2,3,5-tri-O-benzoyl-2-C-methyl ribofuranose.
was then identified as a suitably protected precursor for the synthesis of the classic 2’-C-Methyl ribonucleosides (scheme 6), and may be coupled with most nucleobases under persilylation conditions. The reaction proceeds through a 1,2-oxonium intermediate. This coupling is stereoselective, giving the beta nucleoside derivative. The choice of the benzoyl ester protecting groups appears to be critical for achieving this beta stereoselectivity.