title: N1-hydroxylated derivatives of chlorpropamide and its analogs as inhibitors of aldehyde dehydrogenase in vivo.
abstract: Certain (arylsulfonyl)urea hypoglycemic drugs exemplified by chlorpropamide (CP) are known to interact pharmacologically with alcohol (ethanol) to elicit a chlorpropamide-alcohol flushing (CPAF) reaction that is reminiscent of the disulfiram-ethanol reaction (DER). In the present structure-activity study, designed to elucidate the mechanism of inhibition of aldehyde dehydrogenase (AlDH) by CP, we discovered that the N1-methoxy derivative of CP 2a was a potent inhibitor of AlDH in vivo similar in activity to that of the N1-ethyl derivative 2b. Both 2a and 2b can release n-propyl isocyanate, a known inhibitor of AlDH, nonenzymatically. However, (arylsulfonyl)carbamates that are structurally analogous to 2a were also active inhibitors of AlDH, whereas the corresponding (arylsulfonyl)carbamate analogs of 2b were uniformly without activity. We propose a mechanism of bioactivation of 2a and its analogs that involves initial O-demethylation followed by disproportionation and solvolysis of the intermediate formed to release nitroxyl, the putative inhibitor of AlDH.
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis.
authors.forename: M J
authors.initials: MJ
authors.lastname: Lee
authors.forename: J A
authors.initials: JA
authors.lastname: Elberling
authors.forename: H T
authors.initials: HT
authors.lastname: Nagasawa
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000097:blood; D000818:Animals; D002747:Chlorpropamide / Q000031:analogs & derivatives*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D013453:Sulfonylurea Compounds; D000444:Aldehyde Dehydrogenase; D002747:Chlorpropamide