Patent Watch

November 11, 2013

RdRp inhibitors are a potential flu therapy. Inventor M. O. H. Clarke discloses 2′-substituted carba-nucleoside analogues represented by formula 1. These compounds inhibit RNA-dependent RNA polymerase (RdRp) of the Orthomyxoviridae virus family, which includes influenza A and B viruses. The compounds may provide treatments for influenza infections.

General formula for RdRp inhibitors and representative examples

The influenza virus is a single-strand, negative-sense, segmented RNA orthomyxovirus that uses RdRp to synthesize the viral RNAs needed for replication. Some new anti-influenza agents such as the experimental drug favipiravir and the compounds described in this patent application introduce a promising mechanism for treating influenza. These compounds inhibit influenza RdRp by targeting the virus replication process to stop or slow its replication. This may provide an alternative treatment for influenza infections that has low potential for drug resistance.

Representative examples 2–5 of formula 1 compounds are shown in the figure. The inventor used two biological assays to assess the activity of the compounds: the influenza RNA polymerase inhibition assay and the normal human bronchial/tracheal epithelial cell influenza infection assay. Data from the second of these assays for the four representative compounds are shown in the table.

Example Infl A PC/1/73,
EC50 (μM)
Infl B Lee/40,
EC50 (μM)
2 21 51
3 0.9 0.9
4 > 100 > 100
5 > 200 > 200

Additional information

The most severe influenza infections are caused by the type A virus that infects humans and other species such as birds and pigs. It has caused all known pandemics and most epidemics.

The type A virus undergoes sudden genetic changes called antigenic shifts that are associated with changes in the hemagglutinin (H) and neuraminidase (N) proteins; such changes introduce new strains of the virus. Scientists have identified 15 hemagglutinin (H1–H15) and 9 neuraminidase (N1–N9) subtypes of the type A virus. The virus is named according to the hemagglutinin and neuraminidase subtypes, for example, H1N1, H1N2, and H3N2.

Influenza is a highly contagious acute respiratory infection that infects 10–20% of the population annually. It is associated with significant morbidity and mortality in high-risk patient populations and is responsible for >200,000 hospitalizations and 20,000–35,000 deaths annually in the United States. Globally, the disease results in 250,000–500,000 deaths annually. It causes major pandemics; the most devastating was the 1918–1919 pandemic (the “Spanish flu”). It was caused by H1N1 virus and resulted in 50–100 million deaths.

Vaccination, the first known influenza therapy, was developed in the 1940s. It is still the primary method for prophylactic protection from the virus. The production of vaccines, however, requires 6–8 months, and the vaccine should be administered ≈4 weeks before potential infection to be effective. Vaccines lose their effectiveness quickly because of viral mutations, and they are ineffective against new pandemic forms.

The antiviral drugs amantadine (Symmetrel) and rimantadine (Flumadine) block the ion channel M2-protein responsible for uncoating the virus. They are mostly ineffective because of virus resistance, and they cause severe side effects.

Neuraminidase inhibitors (NAIs) are currently the most effective direct-acting drugs approved to treat influenza A and B virus infections. NAIs block the enzyme neuraminidase, which cleaves the connection to sialic acid and frees the emerging viruses after replication. When these connections are intact, viruses clump together and lose their ability to spread to other cells. Known neuraminidase inhibitors include zanamivir (Relenza), ostelamivir (Tamiflu), and peramivir. Recently, however, some influenza virus strains have developed resistance to NAIs.

Some experimental influenza treatments include

  • combination therapies, including the triple-combination antiviral drug regimen that consists of amantadine, oseltamivir, and ribavirin and the double combination of favipiravir and oseltamivir;
  • influenza RdRp inhibitors such as favipiravir and the compounds described in this application; and
  • a host-targeted method in which the sialidase fusion protein DAS181 effectively cleaves sialic acid receptors used by influenza viruses in the respiratory epithelial cells. DAS181 has shown potent inhibition of virus replication, with EC50 values in the range 0.04–0.9 nM.

(Gilead Sciences [Foster City, CA]. WIPO Publication 2013138236, Sept 19, 2013; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.