PF 05175157 is an inhibitor of acetyl-CoA carboxylase 1 (ACC1) and ACC2 (IC50s = 27, 33, 23.5, and 50.4 nM for human ACC1, human ACC2, rat ACC1, and rat ACC2, respectively

ACC2 (rat):50.4 nM, ACC2 (human):33.0 nM , ACC1 (rat):23.5 nM , ACC1 (human):27.0 nM

PF-05175157 induced a reduction of the viral load in serum and kidney in WNV-infected mice, unveiling its therapeutic potential for the treatment of chronic kidney disease associated with persistent WNV infection.

Pharmacokinetics was analyzed after a single oral dose of the compounds (in a 0.5% methyl cellulose suspension) administered to fasted male mice. A dose of 15 mg/kg for PF-05175157 or 100 mg/kg in the case of PF-05206574 and PF-06256254 was analyzed. Antiviral activity in vivo was determined using eight-week-old Swiss albino CD-1 female mice. Animals were treated with PF-05175157 (20 mg/kg) suspended in 1% carboxymethylcellulose by oral gavage twice a day from 1 d before infection with WNV (1 × 10^4 PFU/mouse intraperitoneally) and up to 7 days post-infection. Control mice were treated in parallel with drug vehicle (carboxymethylcellulose). For experiments evaluating the effect of genetic deletion of ACC2 gene on WNV infection, a breeding colony of C57BL/6 ACC2-/- mice was established from two heterozygous Acabtm1Dejs females . Age- and sex-matched eight-week-old ACC2-/- and control wild type (WT) mice were challenged with WNV (1 × 10^4 PFU/animal.). Animals were monitored daily and received water and food ad libitum.