Orally active aldose reductase inhibitors derived from bioisosteric substitutions on tolrestat.
Wrobel J, Millen J, Sredy J, Dietrich A, Kelly JM, Gorham BJ, Sestanj K.
A series of aldose reductase inhibitors was prepared in which structural modifications were made to three positions of the potent, orally active inhibitor tolrestat (1), namely, the 6-methoxy substituent, thioamide sulfur, and the N-methyl moiety. These compounds were evaluated in two in vitro systems: an isolated enzyme preparation from bovine lens to assess their intrinsic inhibitory activity and an isolated rat sciatic nerve assay to determine their ability to penetrate membranes of nerve tissue. These compounds were also evaluated in vivo as inhibitors of galactitol accumulation in the lens, sciatic nerve, and diaphragm of galactose-fed rats. Bioisosteric replacement of the 6-methoxy group of 1 with a methylthio substituent gave 5, and replacement of the thioamide substituent of 1 with a cyanoamidine gave 7. Both 5 and 7 retained high in vitro potency but were less potent in vivo than 1. Replacement of the tolrestat N-methyl group by a carbomethoxy moiety gave 10 and led to a substantial reduction in activity in each of the three assays employed. However, this same structural modification on oxo-tolrestat (2) led to 11 and resulted in an enhancement of the intrinsic activity and a comparable in vivo potency. The isolated nerve data suggest that some compounds in these series do not readily penetrate into peripheral nerves, and this presumably is a factor in their lack of oral activity.