2-Substituted thiazolidine-4(R)-carboxylic acids as prodrugs of L-cysteine. Protection of mice against acetaminophen hepatotoxicity

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Abstract
A number of 2-alkyl- and 2-aryl-substituted thiazolidine-4(R)-carboxylic acids were evaluated for their protective effect against hepatotoxic deaths produced in mice by LD90 [90% lethal dose] doses of acetaminophen. 2(RS)-Methyl-, 2(RS)-n-propyl- and 2(RS)-n-pentylthiazolidine-4(R)-carboxylic acids (compounds 1b, d, e, respectively), were nearly equipotent in their protective effect based on the number of surviving animals at 48 h as well as by histological criteria. 2(RS)-Ethyl-, 2(RS)-phenyl- and 2(RS)-(4-pyridyl)thiazolidine-4(R)-carboxylic acids (compounds 1c, f, g) were less protective. The enantiomer of 1b, i.e., 2(RS)-methylthiazolidine-4-(S)-carboxylic acid (2b), was totally ineffective in this regard. Thiazolidine-4(R)-carboxylic acid (1a), but not its enantiomer, 2a, was a good substrate for a solubilized preparation of rat liver mitochondrial proline oxidase [Km = 1.1 .times. 10-4 M; Vmax = 5.4 .mu.mol/min per (mg of protein)]. Compound 1b was not a substrate for proline oxidase but dissociated to L-Cys in this system. At physiological pH and temperature, the hydrogens on the methyl group of 1b underwent deuterium exchange with solvent D2O (k1 = 2.5 .times. 10-5 s), suggesting that opening of the thiazolidine ring must have taken place. 1b labeled with 14C in the 2 and methyl positions as rapidly metabolized by the rat to produce 14CO2, 80% of the dose being excreted in this form in the expired air after 24 h. These 2-substituted thiazolidine-4(R)-carboxylic acids are apparently prodrugs of L-Cys that liberate this sulfhydryl amino acids in vivo by nonenzymatic ring opening, followed by solvolysis.