OBJECTIVE —The purpose of this study was to evaluate the efficacy of fidarestat, a novel aldose reductase (AR) inhibitor, in a double-blind placebo controlled study in patients with type 1 and type 2 diabetes and associated peripheral neuropathy. RESEARCH DESIGN AND METHODS —A total of 279 patients with diabetic neuropathy were treated with placebo or fidarestat at a daily dose of 1 mg for 52 weeks. The efficacy evaluation was based on change in electrophysiological measurements of median and tibial motor nerve conduction velocity, F-wave minimum latency, F-wave conduction velocity (FCV), and median sensory nerve conduction velocity (forearm and distal), as well as an assessment of subjective symptoms. RESULTS —Over the course of the study, five of the eight electrophysiological measures assessed showed significant improvement from baseline in the fidarestat-treated group, whereas no measure showed significant deterioration. In contrast, in the placebo group, no electrophysiological measure was improved, and one measure significantly deteriorated (i.e., median nerve FCV). At the study conclusion, the fidarestat-treated group was significantly improved compared with the placebo group in two electrophysiological measures (i.e., median nerve FCV and minimal latency). Subjective symptoms (including numbness, spontaneous pain, sensation of rigidity, paresthesia in the sole upon walking, heaviness in the foot, and hypesthesia) benefited from fidarestat treatment, and all were significantly improved in the treated versus placebo group at the study conclusion. At the dose used, fidarestat was well tolerated, with an adverse event profile that did not significantly differ from that seen in the placebo group. CONCLUSIONS —The effects of fidarestat-treatment on nerve conduction and the subjective symptoms of diabetic neuropathy provide evidence that this treatment alters the progression of diabetic neuropathy.

https://care.diabetesjournals.org/content/diacare/24/10/1776.full.pdf

Clinical Efficacy of Fidarestat, a Novel Aldose Reductase Inhibitor, for Diabetic Peripheral Neuropathy: A 52-week multicenter placebo-controlled double-blind parallel group study

Catalytic asymmetric chemoselective 1,3-dipolar cycloadditions of an azomethine ylide with isatin-derived imines: diastereo- and enantioselective construction of a spiro[imidazolidine-2,3′-oxindole] framework

Applications of fluorine-containing amino acids for drug design.

Aldose reductase and aldehyde reductase belong to the aldo-keto reductase superfamily of enzymes whose members are responsible for a wide variety of biological functions. Aldose reductase has been identified as the first enzyme involved in the polyol pathway of glucose metabolism which converts glucose into sorbitol. Glucose over-utilization through the polyol pathway has been linked to tissue-based pathologies associated with diabetes complications, which make the development of a potent aldose reductase inhibitor an obvious and attractive strategy to prevent or delay the onset and progression of the complications. Structural studies of aldose reductase and the homologous aldehyde reductase in complex with inhibitor were carried out to explain the difference in the potency of enzyme inhibition. The aim of this review is to provide a comprehensive summary of previous studies to aid the development of aldose reductase inhibitors that may have less toxicity problems than the currently available ones.

Selectivity determinants of the aldose and aldehyde reductase inhibitor-binding sites.

An efficient green chemical approach for the synthesis of structurally diverse spiroheterocycles with fused heterosystems

Optically active and racemic 2-substituted-6-fluoro-2,3-dihydrospiro[4H-1-benzopyran-4, 4'-imidazolidine]-2',5'-diones were synthesized from (+)-, (-)-, and (+-)-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid. These compounds were then evaluated for in vitro and in vivo aldose reductase inhibitory activity. The 2S,4S isomers were found to be more potent aldose reductase inhibitors than the other corresponding stereoisomers. Among these compounds, (2S,4S)-6-fluoro-2,3-dihydro-2',5'-dioxospiro[4H-1-benzopyran-4, 4'-imidazolidine]-2-carboxamide ((+)-1b, SNK-860, CAS 105300-43-4) showed the most potent in vitro and in vivo activity.

Yamaguchi T

Papers

Synthesis and aldose reductase inhibitory activity of 2-substituted-6-fluoro-2,3-dihydrospiro [4H-1-benzopyran-4, 4'-imidazolidine]-2',5'-diones.