Latent alkyl isocyanates as inhibitors of aldehyde dehydrogenase in vivo.
On the basis of our previous observation that N1-alkyl substituted chlorpropamide derivatives when administered to rats nonenzymatically eliminated n-propyl isocyanate, a known inhibitor of aldehyde dehydrogenase (AlDH), we have synthesized other latentiated n-propyl isocyanates as in vivo inhibitors of AlDH. N1-Allylchlorpropamide 3 was, as expected, a potent inhibitor of hepatic AlDH in rats, as indicated by the 4-fold increase in the levels of ethanol-derived blood acetaldehyde relative to that elicited by chlorpropamide itself. Closely following in activity in decreasing order were N3-(n-propylcarbamoyl)uracil (7),N-(n-propylcarbamoyl)saccharin (6), and the S-(n-propylcarbamoyl) derivative (9) of benzyl mercaptan. However, two hydantoin derivatives, 5 and 8, were totally inactive in inhibiting AlDH in vivo. A prodrug of N1-ethylchlorpropamide, viz., its N3-trifluoroacetyl derivative (4b), was a good in vivo inhibitor of AlDH, mimicking the activity of the parent N1-ethylchlorpropamide. These results suggest that latent alkyl isocyanates are inhibitors of AlDH, giving further support to the hypothesis that the inhibition of AlDH in vivo by the hypoglycemic agent chlorpropamide may be due to the release of n-propyl isocyanate following metabolic bioactivation.
Nagasawa
H T
HT
Medical Research Laboratory, VA Medical Center, Minneapolis, Minnesota.
Elberling
J A
JA
Goon
D J
DJ
Shirota
F N
FN
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D017953:Isocyanates / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D017953:Isocyanates; D000444:Aldehyde Dehydrogenase