Carbamate ester prodrugs of dopaminergic compounds: synthesis, stability, and bioconversion.
Various carbamic acid esters (CAE) of a new class of dopaminergic drugs, 5-substituted 8-chloro-7-hydroxy-3-methyl-2,3,4,5- tetrahydro-1 H-3-benzazepines, were synthesized and evaluated as prodrug forms with the aim of protecting the parent phenols against first-pass metabolism following oral administration. Monosubstituted CAE were found to be highly unstable at pH 7.4 and 37 degrees C, the half-lives of hydrolysis being between 4 and 40 min. Plasma from various species catalyzed the hydrolysis of the carbamates. N,N-Disubstituted carbamates, on the other hand, were stable both in buffer and plasma solutions. They showed a very potent inhibition of butyrylcholinesterase (EC 3.1.1.8), but were less potent inhibitors of the specific erythrocyte acetylcholinesterase (EC 3.1.1.17). In vitro incubations of an N,N-dimethylsubstituted carbamate ester (10) with liver microsomes from mouse and rat showed an appreciable formation of the parent phenolic compound. This bioconversion is suggested to occur via an initial cytochrome P-450-catalyzed hydroxylation to give an N-hydroxymethyl derivative which spontaneously decomposes to the N-monomethylcarbamate. It is concluded that N,N-disubstituted carbamate esters may be potentially useful prodrugs for the 7-hydroxy-3-benzazepines, whereas N-monosubstituted carbamates appear to be too chemically and enzymatically labile.
Department of Metabolism, Novo Nordisk, Bagsvaerd, Denmark.
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Hansen
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Faarup
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Bundgaard
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001711:Biotransformation; D002091:Butyrylcholinesterase / Q000378:metabolism; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D004355:Drug Stability; D004912:Erythrocytes / Q000201:enzymology; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains
D000596:Amino Acids; D002219:Carbamates; D002800:Cholinesterase Inhibitors; D015259:Dopamine Agents; D011355:Prodrugs; D002091:Butyrylcholinesterase