NS5A inhibitors

In the initial clinical study with DCV, which represented a proof-of-concept trial for the HCV NS5A inhibitor mechanism, GT-1 HCV-infected subjects were administered single doses of 1,10, and 100 mg of the drug, and plasma viral load was followed for 7 days. A reduction in viremia that was both rapid and profound was observed at all doses, with mean declines in viral load of 1.8, 3.2, and 3.3 logio at the 1, 10, and 100 mg doses, respectively. Most interestingly, those receiving the highest dose experienced an... 

Sofosbuvir was also studied with other oral DAA that have a different mechanism of action, with the ultimate goal of elimination of PeglFN and RBV, increased efficacy, decreased duration of treatment, and minimized drug toxicity. These DAA include NS5A inhibitors (daclatasvir, ledipasvir, GS-5816, and ACH-3102), NS3/4A protease inhibitors (simeprevir and GS-9451), and the non-nucleoside polymerase inhibitor (GS-9669). Among them, a fixed dose combination study of SOF and ledipasvir, Harvoni, was the first approved interferon-free DAA combination for the treatment of HCV infection. 

A similar reduction towards a primary amine intermediate was reported by scientists at Merck (Fig. 29). The target in this case was the HCV NS5a inhibitor MK-8742, and a key step was a highly enantioselective ATH of a C=N bond. Among the catalysts investigated, the best one proved to be the tethered catalyst reported by Wills et al. The synthesis of the complex target requires simple starting materials and just nine linear steps for completion [100]. 

ABT-450 (structure not disclosed, Abbott / Enanta) is a once-daily, ritonavir-boosted macrocyclic HCV PI. This compound is being developed in Phase III trials in IFN-free all-oral regimens with several other direct-acting antiviral agents including ABT-267 (an NS5A inhibitor) and ABT-333 (a nonnucleoside polymerase inhibitor). ACH-1625 (strueture not reported, Achillion) is a once-daily, linear HCV PI currently in Phase n clinieal trials. ... 

Several classes of non-covalent substrate based inhibitors have been reported, and are grouped below based on the nature of the C-terminal group interacting with the catalytic triad of the enzyme. The majority of the reported inhibitors are based on the N-terminal product of a modified substrate of the NS5A/5B cleavage side or to a lesser extent of the NS4A/4B substrate peptide. 

The first protease inhibitor studied in human clinical trials was ciluprevir (BILN-2061), whose discovery was predicated on earlier studies that identified 54, a 6 amino acid N-terminal cleavage product of an NS5A/5B substrate, as a competitive inhibitor of NS3 [103,104], Although the development of ciluprevir was halted due to cardiotoxicity in animals, it demonstrated that a potent... 

Daclatasvir (Daklinza) The First-in-Class HCV NS5A Replication Complex Inhibitor... 

Currently, three categories of anti-HCV DAAs have been approved, and the nomenclature is based on which viral function is inhibited or affected. The categories are NS3/NS4A protease inhibitors [PI, e.g., boceprevir (2), telaprevir (3), and simeprevir (4)], NS5A protein inhibitors [e.g., ledipasvir (5)], and NS5B RNA-dependent RNA polymerase (RdRp) inhibitors (e.g., sofosbuvir). The last category can be divided further into two subclasses nucleoside/nucleotide polymerase inhibitors (NPI) and nonnucleoside polymerase inhibitors (NNPI). 

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