Amine prodrugs which utilize hydroxy amide lactonization. I, A potential redox-sensitive amide prodrug

Several amides of 3-(3',6'-dioxo-2',4'-dimethylcyclohexa-1',4'-diene)-3,3- dimethylpropionic acid (2) have been synthesized and tested as model redox-sensitive pro-prodrugs of amines. The reduction of these model pro-prodrugs generated hydroxy amide intermediates 4a-4h,...

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Bibliographic Details
Published in:Pharmaceutical research 1991-03, Vol.8 (3), p.323-330
Main Authors: AMSBERRY, K. L, BORCHARDT, R. T
Format: Article
Language:English
Subjects:
Amides - metabolism
Amines - metabolism
Biological and medical sciences
Chromatography, High Pressure Liquid - methods
Cyclohexanones - metabolism
General pharmacology
Hydroquinones - metabolism
Kinetics
Lactones - metabolism
Medical sciences
Oxidation-Reduction
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Prodrugs - chemical synthesis
Prodrugs - metabolism
Propionates - metabolism
Quinones - metabolism
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Summary:Several amides of 3-(3',6'-dioxo-2',4'-dimethylcyclohexa-1',4'-diene)-3,3- dimethylpropionic acid (2) have been synthesized and tested as model redox-sensitive pro-prodrugs of amines. The reduction of these model pro-prodrugs generated hydroxy amide intermediates 4a-4h, the lactonization of which resulted in amine release. The rates of lactonization of 4a-4h were investigated at pH 7.4 and 37 degrees C. The half-lives for appearance of the product lactone 1a from these intermediates were found to range from 1.4 to 3.4 min. With such rapid lactonization rates, it is believed that reduction will be the rate-limiting step in the two-step conversion of the pro-prodrug to the amine.
ISSN:0724-8741
1573-904X
DOI:10.1023/A:1015885213625