title: Cleavage of tertiary amidomethyl ester prodrugs of carboxylic acids by rat liver homogenates.
abstract: The hydrolysis of tertiary amidomethyl ester prodrugs of carboxylic acids by rat liver homogenates is reported. Amidomethyl esters are rapidly and quantitatively converted to the corresponding acid and secondary amide. Reactivity is inversely dependent upon the molar refractivity and lipophilicity of the ester, as well as with steric bulk in the carboxylic acid moiety. In contrast to chemical and plasma hydrolyses, no dependence upon the pK(a) of the carboxylate leaving group was observed, nor was there any dependence upon the amide N-substituent. The rate of decomposition was inhibited by the carboxylesterase inhibitor eserine but not by the cytochrome P450 inhibitor SKF-525A, indicating the involvement of esterases in the hydrolysis reaction. These results indicate that amidomethyl esters may be expected to be readily cleaved in vivo.
authors.affiliation: Chemistry Department, The Open University, Milton Keynes, UK.
authors.forename: J
authors.initials: J
authors.lastname: Iley
authors.forename: E
authors.initials: E
authors.lastname: Mendes
authors.forename: R
authors.initials: R
authors.lastname: Moreira
authors.forename: S
authors.initials: S
authors.lastname: Souza
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D019817:Benzoic Acid / Q000493:pharmacokinetics; D002264:Carboxylic Acids / Q000493:pharmacokinetics*; D002995:Clofibric Acid / Q000493:pharmacokinetics; D004008:Diclofenac / Q000493:pharmacokinetics; D004347:Drug Interactions; D004952:Esters / Q000493:pharmacokinetics*; D006867:Hydrolases / Q000502:physiology*; D006868:Hydrolysis; D007052:Ibuprofen / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D009288:Naproxen / Q000493:pharmacokinetics; D010830:Physostigmine / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D011339:Probenecid / Q000493:pharmacokinetics; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012031:Refractometry; D012995:Solubility; D013329:Structure-Activity Relationship; D013997:Time Factors; D014635:Valproic Acid / Q000493:pharmacokinetics
chemical_list: D000577:Amides; D002264:Carboxylic Acids; D004952:Esters; D011355:Prodrugs; D004008:Diclofenac; D002995:Clofibric Acid; D009288:Naproxen; D014635:Valproic Acid; D019817:Benzoic Acid; D010830:Physostigmine; D011335:Proadifen; D006867:Hydrolases; D011339:Probenecid; D007052:Ibuprofen