Glycolamide esters as biolabile prodrugs of carboxylic acid agents: synthesis, stability, bioconversion, and physicochemical properties.
Benzoic acid esters of various substituted 2-hydroxyacetamides (glycolamides) were found to be hydrolyzed extremely rapidly in human plasma solutions, the half-lives of hydrolysis being less than 5 s in 50% plasma solutions for some N,N-disubstituted glycolamide esters. The rapid rate of hydrolysis could be largely attributed to cholinesterase (also called pseudocholinesterase) present in plasma. From a study of a variety of substituted glycolamide esters and structurally related esters, the most prominent structural requirement needed for a rapid rate of hydrolysis was found to be the glycolamide ester structure combined with the presence of two substituents on the amide nitrogen atom. A structural similarity of such esters with benzoylcholine, a good substrate for cholinesterase, was put forward. Esters of N,N-disubstituted glycolamides are suggested to be a useful biolabile prodrug type for several carboxylic acid agents. The esters combine a high susceptibility to undergo enzymatic hydrolysis in plasma with a high stability in aqueous solution. Furthermore, as demonstrated with the benzoic acid model esters, it is feasible to obtain ester derivatives with almost any desired water solubility or lipophilicity with retainment of marked lability to enzymatic hydrolysis.
Nielsen
N M
NM
Royal Danish School of Pharmacy, Department of Pharmaceutical Chemistry AD, Copenhagen, Denmark.
Bundgaard
H
H
D001711:Biotransformation; D002264:Carboxylic Acids / Q000378:metabolism* / Q000493:pharmacokinetics; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002918:Chymotrypsin; D004355:Drug Stability; D004952:Esters / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D006016:Glycolates / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D004364:Pharmaceutical Preparations / Q000138:chemical synthesis*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
D002264:Carboxylic Acids; D004952:Esters; D006016:Glycolates; D004364:Pharmaceutical Preparations; D011355:Prodrugs; D002918:Chymotrypsin