Small-molecule inhibitors of hepatitis C virus (HCV) non-structural protein 5A (NS5A): a patent review (2010-2015)

ABSTRACT

Introduction: Non-structural 5A (NS5A) protein has achieved a considerable attention as an attractive target for the treatment of hepatitis C (HCV). A number of novel NS5A inhibitors have been reported to date. Several drugs having favorable ADME properties and mild side effects were launched into the pharmaceutical market. For instance, daclatasvir was launched in 2014, elbasvir is currently undergoing registration, ledipasvir was launched in 2014 as a fixed-dose combination with sofosbuvir (NS5B inhibitor).

Areas covered: Thomson integrity database and SciFinder database were used as a valuable source to collect the patents on small-molecule NS5A inhibitors. All the structures were ranked by the date of priority. Patent holder and antiviral activity for each scaffold claimed were summarized and presented in a convenient manner. A particular focus was placed on the best-in-class bis-pyrrolidine-containing NS5A inhibitors.

Expert opinion: Several first generation NS5A inhibitors have recently progressed into advanced clinical trials and showed superior efficacy in reducing viral load in infected subjects. Therapy schemes of using these agents in combination with other established antiviral drugs with complementary mechanisms of action can address the emergence of resistance and poor therapeutic outcome frequently attributed to antiviral drugs.

KEYWORDS:

• NS5A inhibitors
• hepatitis C virus
• HCV
• drug design

Article highlights

• NS5A inhibitors have recently emerged as promising anti-hepatitis C agents.

• The chemical space of NS5A inhibitors is rather poorly defined and still limited to several chemotypes.

• Since the best ‘caps’ were identified special attention was payed to the ‘linker’ area.

• 1^st generation of HCV therapeutics were replaced by the 2^nd generation with an improved antiviral efficiency particularly against resistant types.

• During clinical trials, several NS5A inhibitors demonstrated superior efficacy in reducing of viral load in infected subjects compared to many other antiviral therapeutics.

This box summarizes key points contained in the article.

Declaration of interest

The authors knowledge financial support from Russian Scientific Fund (14-34-00017). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Additional information

Funding

This work was supported by Russian Scientific Fund [grant number 14-34-00017].