Pimodivir

Pimodivir (VX-787, JNJ872, JNJ 63623872) is a first-in-class, orally bioavailable inhibitor of influenza virus polymerase PB2 subunit with Kd of 1 μM, 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. Pimodivir (VX-787) is very potent against influenza A strains, including pandemic 2009 H1N1 and avian H5N1. Pimodivir (VX-787) 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. (In Vivo) :Pimodivir (2, 6, and 20 mg/kg/day, p.o.) and GS 4071 (20 mg/kg/day) completely prevent death in the H1N1pdm virus infection in mice. Pimodivir (20 mg/kg/day) is more effective than GS 4071 (20 mg/kg/day) in improving body weight and reducing the severity of lung infection. Moreover, Pimodivir (VX-787) shows 100% survival in a +48 h delay to treatment mouse influenza model at 10, 3 and 1 mpk (BID x 10 days) whereas the SOC, GS 4071, provide no survival benefit in this model at 10 mpk. Pimodivir (VX-787; 1, 3, or 10 mg/kg, bid) provided complete survival, with a dose-dependent reduction in BW loss of the mice.