CELLULAR-METABOLISM AND ANTIINFLUENZA ACTIVITY OF 1,3,4-THIADIAZOL-2-YLCYANAMIDE (LY217896)

LY217896 (1,3,4-thiadiazol-2-ylcyanamide) is a 2-substituted thiadiazole that is an effective inhibitor of influenza A and B viruses in vitro and in the mouse infection model. The in vitro anti-influenza activity of LY217896 is reversed by a 10-fold excess amount of guanine or guanosine. LY217896 (1 or 10 mug ml-1) effected a selective 60% decrease in the levels of intracellular pools of GTP in MDCK cells. The extent of cytotoxicity of LY217896 is positively correlated with the amount of LY217896 metabolite formed intracellularly. A cell line, derived from parental MDCK cells, was selected for resistance to 50 mug of LY217896 per ml. Unlike parental MDCK cells, the resistant cells were able to undergo log phase replication in LY217896 (25 g ml-1) and were unable to metabolize the compound. Furthermore, LY217896 had no antiviral activity against influenza A/Ann Arbor (IC50 >200 mug ml-1) or vaccinia virus (IC50 = 135 mug ml-1) in resistant cells. In contrast, LY217896 inhibited influenza A/Ann Arbor (IC50 = 0.5 mug ml-1) or vaccinia virus (IC50 = 0.13 mug ml-1) in the parental MDCK cells. A thiadiazole, with a guanidinyl group in the 2 position, and ribavirin were active in both the parental cells and resistant cells. Nicotinamide (up to 240-fold excess) did not reverse the anti-influenza activity of LY217896 in vitro or in the mouse infection model. A 10-fold excess of nicotinamide reversed the cytotoxicity of 2-aminothiadiazole but not that of LY217896.