Acyl, N-protected alpha-aminoacyl, and peptidyl derivatives as prodrug forms of the alcohol deterrent agent cyanamide.
Cyanamide (H2NC identical to N), a potent aldehyde dehydrogenase (AlDH) inhibitor that is used therapeutically as an alcohol deterrent agent, is known to be rapidly metabolized and excreted in the urine as acetylcyanamide (1). On the basis of our observation that 1 is deacetylated to cyanamide in vivo, albeit very slightly, thereby serving as a precursor of prodrug form of the latter, several acyl derivatives of cyanamide were synthesized specifically as prodrugs, including benzoylcyanamide (2), pivaloylcyanamide (3), and 1-adamantoylcyanamide (4), as well as long- and medium-chain fatty acyl derivatives such as palmitoyl- (6), stearoyl- (7), and n-butyrylcyanamide (5). N-Protected alpha-aminoacyl and peptidyl derivatives of cyanamide were also synthesized, and these include N-carbobenzoxyglycyl- (10), hippuryl- (13), N-benzoyl-L-leucyl- (14), N-carbobenzoxyglycyl-L-leucyl- (18), N-carbobenzoxy-L-pyroglutamyl- (22), L-pyroglutamyl-L-leucyl- (19), and L-pyroglutamyl-L-phenylalanylcyanamide (20). All of these prodrugs of cyanamide raised ethanol-derived blood acetaldehyde levels in rats significantly over controls 3 h after ip drug administration, and some of these were still capable of elevating blood acetaldehyde 16 h post drug administration. A selected group of cyanamide prodrugs were also evaluated by the oral route of administration and showed nearly equivalent activity as the ip route in elevating ethanol-derived blood acetaldehyde. These results suggest potential utility of these prodrugs as deterrent agents for the treatment of alcoholism.
D000215:Acylation; D000427:Alcohol Deterrents / Q000138:chemical synthesis* / Q000494:pharmacology; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D001711:Biotransformation; D003484:Cyanamide / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D003486:Cyanides / Q000138:chemical synthesis*; D051381:Rats
D000427:Alcohol Deterrents; D003486:Cyanides; D003484:Cyanamide; D000444:Aldehyde Dehydrogenase