Novel prodrugs of cyanamide that inhibit aldehyde dehydrogenase in vivo

Journal of Medicinal Chemistry
F N ShirotaH T Nagasawa

Abstract

S-Methylisothiourea (4), when administered to rats followed by a subsequent dose of ethanol, gave rise to a 119-fold increase in ethanol-derived blood acetaldehyde (AcH) levels-a consequence of the inhibition of hepatic aldehyde dehydrogenase (A1DH)-when compared to control animals not receiving 4. The corresponding O-methylisourea was totally inactive under the same conditions, suggesting that differential metabolism may be a factor in this dramatic difference between the pharmacological effects of O-methylisourea and 4 in vivo. The S-n-butyl- and S-isobutylisothioureas (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, blood ethanol levels of all experimental groups were indistinguishable from controls. Pretreatment of the animals with 1-benzylimidazole, a known inhibitor of the hepatic mixed function oxidases, followed sequentially by either 8, 9, or 10 plus ethanol, reduced blood AcH levels by 66-88%, suggesting that the latter compounds were being oxidatively metabolized to a common product that led to the inhibition of AcH metabolism. In support of this, when 8 was incubated in vitro w...Continue Reading

References

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Citations

Jul 8, 2010·Archives of Pharmacal Research·Zygmunt KazimierczukStanislaw J Chrapusta
Mar 20, 2002·Addiction Biology·Hiroshi Matsumoto, Yuko Fukui
Jul 26, 2017·Frontiers in Microbiology·Muriel C F van TeeselingFelipe Cava
Dec 7, 2011·Organic Letters·Ryan M StolleyJanis Louie
Nov 15, 2017·Organic Letters·Antoine NiteletGwilherm Evano

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