Biotransformation of the antiviral agent 1,3,4-thiadiazol-2-ylcyanamide (LY217896) and characteristics of a mesoionic ribose metabolite.
The biotransformation of the antiinfluenza agent 1,3,4-thiadiazol-2-ylcyanamide (LY217896, I) was studied. In addition to a urea metabolite (II) formed by transformation of the cyanamide functionality, another highly polar metabolite was found in mouse urine and in BSC-1, MDCK, and other cell culture incubations of [14C]LY217896. Using 13C-labeled LY217896 together with NMR and MS techniques, this highly polar metabolite was identified as a ribose derivative (III), which apparently exists in a mesoionic form (i.e. positive and negative charges within the same ring system). It was also found that this ribose is formed from LY217896 and ribose-1-phosphate in a reaction catalyzed by the enzyme purine nucleoside phosphorylase, but that the reverse reaction (cleavage of the ribose) is not observed under the conditions used. When tested in vitro using the same assay as that used to measure the antiviral activity of LY217896, this ribose and the urea metabolite exhibit essentially no activity. The presence of a ribose has been implicated in the activity of antiviral compounds such as ribavirin and anticancer agents like 2-aminothiadiazole and tiazofurin, which are structurally similar to LY217896. These activities have been postulated to involve either mono- or triphosphorylated forms, or NAD-type analogs. Possible implications of the formation of this mesoionic ribose metabolite for the mechanism of antiviral activity of LY217896 are discussed.
Ehlhardt
W J
WJ
Department of Drug Metabolism, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285.
Wheeler
W J
WJ
Breau
A P
AP
Chay
S H
SH
Birch
G M
GM
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D001711:Biotransformation; D002250:Carbon Radioisotopes; D005260:Female; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008815:Mice, Inbred Strains; D009570:Nitriles / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D051381:Rats; D011916:Rats, Inbred F344; D012266:Ribose / Q000031:analogs & derivatives / Q000302:isolation & purification / Q000378:metabolism* / Q000652:urine; D013056:Spectrophotometry, Ultraviolet; D013830:Thiadiazoles / Q000302:isolation & purification / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine
D000998:Antiviral Agents; D002250:Carbon Radioisotopes; D009570:Nitriles; D013830:Thiadiazoles; C067593:1,3,4-thiadiazol-2-ylcyanamide; C080054:3-ribofuranosyl-N-cyano-2-amino-1,3,4-thiadiazole; D012266:Ribose