Pimodivir is an orally bioavailable inhibitor of influenza A virus polymerases through interaction with the viral PB2 subunit.
Pimodivir rescues macrophages from virus-mediated death at non-cytotoxic concentrations 24 hpi. The EC50 value for Pimodivir are 8 and 12 nM for A(H1N1) and A(H3N2) strains, respectively, whereas the CC50 values are >1 uM, giving selectivity indexes (SI) > 125 and > 83 for A(H1N1) and A(H3N2) strains, respectively. Pimodivir significantly attenuates the transcription of viral M1 RNA in macrophages, which are infected with A(H1N1) or A(H3N2) strains for 8 h. Pimodivir inhibits the transcription of viral but not cellular genes. Pimodivir allows some activation of IAV-mediated expression of several cellular genes, which are involved in tryptophan and nucleotide metabolism. Pimodivir possesses excellent anti-IAV but not immuno/metabolo-modulating effect[2]. Pimodivir is very potent against influenza A strains, including pandemic 2009 H1N1 and avian H5N1[3]. Pimodivir shows potent activity against all influenza A virus strains tested, with an EC50 range of 0.13 to 3.2 nM. Pimodivir-selected PB2 variant viruses maintain susceptibility to neuraminidase inhibitors in vitro[4].
Pimodivir (2, 6, and 20 mg/kg/day, p.o.) and oseltamivir (20 mg/kg/day) completely prevent death in the H1N1pdm virus infection in mice. Pimodivir (20 mg/kg/day) is more effective than oseltamivir (20 mg/kg/day) in improving body weight and reducing the severity of lung infection[1]. Moreover, Pimodivir shows 100% survival in a +48 h delay to treatment mouse influenza model at 10, 3 and 1 mpk (BID × 10 days) whereas the SOC, oseltamivir, provide no survival benefit in this model at 10 mpk[3]. Pimodivir (1, 3, or 10 mg/kg, bid) provided complete survival, with a dose-dependent reduction in BW loss of the mice[4].
References:
[1]. Smee DF, et al. Activities of JNJ63623872 and oseltamivir against influenza A H1N1pdm and H3N2 virus infections in mice. Antiviral Res. 2016 Dec;136:45-50.
[2]. Fu Y, et al. JNJ872 inhibits influenza A virus replication without altering cellular antiviral responses. Antiviral Res. 2016 Sep;133:23-31.
[3]. Boyd MJ, et al. Isosteric replacements of the carboxylic acid of drug candidate VX-787: Effect of charge on antiviral potency and kinase activity of azaindole-based influenza PB2 inhibitors. Bioorg Med Chem Lett. 2015 May 1;25(9):1990-4.
[4]. Byrn RA, et al. Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit. Antimicrob Agents Chemother. 2015 Mar;59(3):1569-82.