Syntheses of tolrestat analogs containing additional substituents in the ring and their evaluation as aldose reductase inhibitors. Identification of potent, orally active 2-fluoro derivatives

Abstract

A series of aldose reductase inhibitors were prepared which were analogues of the potent, orally active inhibitor tolrestat (1). These compounds (5, 7, 9, and 10) have an extra substituent on one of the unoccupied positions on the naphthalene ring of 1. Primary amide prodrugs of several members from the series 5 and 7, namely 6 and 8, respectively, were also prepared. 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 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. In general, compounds in series 5, 7, 9, and 10 were potent inhibitors of bovine lens aldose reductase. 2-Halo-substituted analogues from the series 5, 7, and 9 exhibited high activity in the nerve of the 4-day-galactose-fed rat, and in several instances, the primary amide prodrug 8 enhanced the in vivo potency of the respective carboxylic acid 7. Two 2-fluoro-derivatives, 8a and 9a, had especially high activity in vivo and were chosen for additional studies. These compounds were found to be approximately equipotent to tolrestat in the sciatic nerve of the galactose-fed rat and the STZ rat, as judged by their ED50's in these assays. Although primary amide analogue 8a did not have intrinsic inhibitory activity toward aldose reductase, it was metabolized to an active form in vivo and also in vitro within the sciatic nerve.

On the stereochemistry of the Baker's Yeast-mediated reduction of regioisomeric unsaturated aldehydes: Examples of enantioselectivity switch promoted by substrate-engineering

“…1c) was compared with that of the deuterated saturated alcohol 21 (Fig. 1b) obtained by BY fermentation of the corresponding cinnamaldehyde (E)-14 [17]. The signal assignment was performed by considering the 1 H NMR spectrum of the synthetic saturated alcohol 16 (Fig.…”

Recent advances in aldose reductase inhibitors: potential agents for the treatment of diabetic complications

“…A 3-thiazolidineacetic acid derivative (20), which can be regarded as a cyclic derivative of epalrestat, has been reported to be a potent ARI with an IC 50 value of 9 nM [44]. Inst.…”

“…These compounds can be divided into two general classes, those containing a carboxylic acid moiety and those having a cyclic imide represented by a spirohydantoin or related ring system [19][20][21][22]. However, arylsulfonylnitromethanes have recently emerged as a new class.…”

Molecular Modeling and Structure-based Drug Discovery Studies of Aldose Reductase Inhibitors

“…There exist a variety of structurally diverse aldose reductase inhibitors (ARIs) (Figure 2). These compounds can be divided into two general classes, those containing a carboxylic acid moiety and those having a cyclic imide represented by a spirohydantoin or related ring system [14,15,16,17]. Recently, however, arylsulphonylnitromethanes have emerged as a new class.…”