N1-alkyl-substituted derivatives of chlorpropamide as inhibitors of aldehyde dehydrogenase.
On the basis of an earlier observation that the N1-ethyl derivative of the hypoglycemic agent chlorpropamide (CP) inhibited aldehyde dehydrogenase (AlDH) in rats without producing hypoglycemia, we undertook a structure-activity study to assess the effect of altering the alkyl substituents at N1 and N3, as well as substituting O for N at the latter position, and evaluated these analogues for their effect on AlDH in vivo and in vitro. Our results suggest that only those CP analogues that can release alkyl isocyanates nonenzymatically inhibited AlDH. Increasing the steric bulk of the N1-alkyl substituent enhanced isocyanate formation and AlDH inhibition. CP analogues that lacked the NH group at N3 or were otherwise incapable of alkyl isocyanate release were inactive.
Nagasawa
H T
HT
Medical Research Laboratories, VA Medical Center, Minneapolis, Minnesota.
Elberling
J A
JA
DeMaster
E G
EG
Shirota
F N
FN
D000079:Acetaldehyde / Q000097:blood; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000478:Alkylation; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D002747:Chlorpropamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology; D015394:Molecular Structure; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000201:enzymology
D001786:Blood Glucose; D000431:Ethanol; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde; D002747:Chlorpropamide