Orally active aldose reductase inhibitors derived from bioisosteric substitutions on tolrestat.

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.

Computer-assisted design and synthesis of novel aldose reductase inhibitors.

The design and synthesis of phenalene 26 (AY-31,358), an unsubstituted analogue of a tolrestat/ICI-105,552 computer-generated hybrid (7), are reported. Compound 7 was designed by the superimposition of the putative low-energy conformers of tolrestat (1) and ICI-105,552 (6). The more rigid aldose reductase inhibitor sorbinil (2) was used as a template to help discern a common pharmacophore in the three inhibitors. Compound 26 was synthesized as a model and was evaluated as an inhibitor of bovine lens aldose reductase. It was found to exhibit good in vitro activity as well as some in vivo activity in the nerve. It was expected that introduction of the trifluoromethyl and methoxy substituents would enhance the biological activity of model compound 26. As a result of a positive Ames test with 26, however, work has now been directed toward modifying the template in a way so as to eliminate the mutagenicity with retention of biological activity.

Synthetic MIF analogues. Part I: synthesis by four-component condensation (4 CC) and classical methods.

Analogues of melanocyte stimulating hormone/release inhibiting hormone (MIF), H-Pro-N-isobutyl-Gly-Gly-NH2, H-Pro-MeLeu-Gly-NH2 (L,L) and H-Pro-MeLeu-Gly-NH2 (L,D) were synthesized by the four-component condensation (4 CC). In addition compounds H-Pro-MeLeu-Ala-NH2 (L,L,D) and H-Pro-MeLeu-Ala-NH2 (L,D,D) were prepared by classical methods.

Antagonism of prostaglandin-induced cyclic AMP accumulation in the rat anterior pituitary in vitro by somatostatin analogues.

The PGE2-induced cyclic AMP accumulation in the rat anterior pituitary in vitro is inhibited by [desamino1]-[desamino1] [descarboxy14]- and [D-Lys4]-somatostatin similarly to somatostatin, while the [descarboxy14]-somatostatin exhibits reduced activity; [D-Lys9]-somatostatin is ineffective at a higher concentration.

Polyol accumulation in galactosemic and diabetic rats: control by an aldose reductase inhibitor.

An orally active inhibitor of aldose reductase, 1,3-dioxo-1H-benz[de]-isoquinoline-2(3H)acetic acid (AY-22,284), prevented cataractous changes in cultured lenses exposed to high concentrations of galactose. When given orally, AY-22,284 markedly decreased the accumulation of polyols in the lenses and sciatic nerves of galactosemic rats and rats with streptozotocin-induced diabetes. In addition, treatment of galactosemic rats with AY-22,284 effectively suppressed the formation of cataracts.