化合物BF738735

BF738735 (Compound 1) strongly inhibits PI4KIIIβ activity in vitro, with an IC ₅₀ of 5.7 nM. BF738735 also impairs PI4KIIIα, but only at an ~300-fold-higher concentration (IC ₅₀ of 1.7 μM). In addition, the activity of BF738735 is analyzed on a set of 150 cellular kinases, including 13 lipid kinases at a concentration of 10 μM. For all kinases, the inhibition is less than 10%, indicating that BF738735 specifically inhibits PI4KIIIβ in vitro. BF738735 exhibits a broad spectrum of antiviral activity, as it inhibits all tested species of enteroviruses and rhinoviruses, with 50% effective concentrations ranging between 4 and 71 nM. BF738735 potently inhibits all viruses tested, with EC ₅₀ s ranging between 4 and 71 nM. The cytotoxicity of BF738735, determined in parallel with the EC ₅₀ and using the same culture conditions for 3 to 4 days, is low, with CC ₅₀ values ranging from 11 to 65 μM, resulting in high selectivity indices. Low concentrations of BF738735 reduce the amount of luciferase to GuaHCl-treated levels, suggesting that the BF738735 blocks viral RNA replication. The EC ₅₀ of BF738735 in this assay is 77 nM, which is comparable to the inhibition observed in the multicycle assay for coxsackievirus serotype B3 (CVB3).

BF738735 is well tolerated by specimens with good plasma levels of the antiviral in circulation and a complete inhibition with 25 mg/kg and some inhibition with 5 mg/kg dose is observed.