M. Tamai, C. Yokoo, M. Murata
Mar 25, 1987
Citations
1
Influential Citations
61
Citations
Quality indicators
Journal
Chemical & pharmaceutical bulletin
Abstract
Ethly (+)-(2S, 3S) -3- [(S) -3-methyl-1- (3-methylbutylcarbamoyl) butylcarbamoyl] -2- oxirane-carboxylate (EST ; la) is expected to be useful as an oral therapeutic agent for muscular dystrophy on the basis of its potent inhibitory activities against the cysteine proteinases involved in the myofibrillar protein degradation that occurs in the disease. Through extensive investigations aimed at developing a new synthetic method for la that would be suitable for industrial application, it has been found that L-arginine can be used as a new, efficient resolving agent to obtain optically pure L-trans-epoxysuccinic acid (3a), and the active ester method using p-nitrophenol is very effective in the coupling reaction of ethyl L-trans-epoxysuccinate (7a) and L-leucine isoamylamide (8a) because of the extremely low formation of by-products.To examine the contribution of the stereochemistry of the trans-epoxysuccinic acid and leucine moieties to the inhibitory activity against cysteine proteinases, the diastereomers (lb-d) of la were synthesized by a similar method and the rate constants of inactivation of papain by la-d were measured. Compound la, having L-trans-epoxysuccinic acid and L-leucine moieties, showed the most potent activity among them.