NOVEL PRODRUGS OF CYANAMIDE THAT INHIBIT ALDEHYDE DEHYDROGENASE IN-VIVO

S-Methylisothiourea (4), when administered to rats followed by a subse quent dose of ethanol, gave rise to a 119-fold increase in ethanol-der ived blood acetaldehyde (AcH) levels--a consequence of the inhibition of hepatic aldehyde dehydrogenase (AIDH)-when compared to control anim als not receiving 4. The corresponding O-methylisourea was totally ina ctive under the same conditions, suggesting that differential metaboli sm may be a factor in this dramatic difference between the pharmacolog ical effects of O-methylisourea and in vivo. The S-n-butyl- and S-isob utylisothioureas (8 and 9, respectively) at doses equimolar to that of 4 were nearly twice as effective in raising ethanol-derived blood AcH , while S-allylisothiourea (10) was slightly less-active. However, blo od ethanol levels of all experimental groups were indistinguishable fr om controls. Pretreatment of the animals with 1-benzylimidazole, a kno wn inhibitor of tile hepatic mixed function oxidases, followed sequent ially by either 8, 9, or 10 plus ethanol, reduced blood AcH-levels by 66-88%, suggesting that the latter compounds were being oxidatively me tabolized to a common product that led to the inhibition of AcH metabo lism. In support of this, when 8 was incubated in vitro with rat liver microsomes coupled to catalase and yeast AlDH, the requirement for mi crosomal activation for the inhibition of AlDH activity was clearly in dicated. We suggest that S-oxidation is involved and that the S-oxides produced in vivo inhibited AlDH directly, or spontaneously released c yanamide, an inhibitor of AlDH. Indeed, incubation of 8 with rat liver microsomes and NADPH gave rise to cyanamide as metabolite, identified as its dansylated derivative. Cyanamide formation was minimal in the absence of coenzyme. Extending the side chain was detrimental, since S -benzylisothiourea (11) and S-n-hexadecylisothiourea (12) were toxic, the latter producing extensive necrosis of the liver and kidneys when administered to rats.