LATENT ALKYL ISOCYANATES AS INHIBITORS OF ALDEHYDE DEHYDROGENASE IN-VIVO

On the basis of our previous observation that N-1-alkyl substituted ch lorpropamide derivatives when administered to rats nonenzymatically el iminated n-propyl isocyanate, a known inhibitor of aldehyde dehydrogen ase (AlDH), we have synthesized other latentiated n-propyl isocyanates as in vivo inhibitors of AlDH. N-1-Allylchlorpropamide 3 was, as expe cted, a potent inhibitor of hepatic AlDH in rats, as indicated by the 4-fold increase in the levels of ethanol-derived blood acetaldehyde re lative to that elicited by chlorpropamide itself. Closely following in activity in decreasing order were N-3-(n-propylcarbamoyl)uracil (7), N-(n-propylcarbamoyl)saccharin (6), and the S-(n-propylcarbamoyl) deri vative (9) of benzyl mercaptan. However, two hydantoin derivatives, 5 and 8, were totally inactive in inhibiting AlDH in vivo. A prodrug of N-1-ethylchlorpropamide, viz., its N-3-trifluoroacetyl derivative (4b) , was a good in vivo inhibitor of AlDH, mimicking the activity of the parent N-1-ethylchlorpropamide. These results suggest that latent alky l isocyanates are inhibitors of AlDH, giving further support to the hy pothesis that the inhibition of AlDH in vivo by the hypoglycemic agent chlorpropamide may be due to the release of n-propyl isocyanate follo wing metabolic bioactivation.