Fidarestat is an aldose reductase inhibitor (IC50 = 0.026 μM using human recombinant enzyme) that also inhibits aldo-keto reductase family 1 member B10 (AKR1B10; IC50 = 33 μM using human recombinant enzyme).1 It decreases sorbitol and myo-inositol levels in the sciatic nerve of rats with diabetes induced by streptozotocin when administered at a dose of 2 mg/kg per day.2 Fidarestat (2 mg/kg per day) decreases nerve fiber abnormalities and reverses slowing of motor nerve conduction velocity (MNCV) in an STZ-induced diabetic rat model of peripheral neuropathy. It decreases the pain threshold in STZ-induced diabetic mice that overexpress human aldose reductase when administered at 4 mg/kg per day.3 Fidarestat (50 mg/kg per day) decreases metastasis in a KM20 human colorectal cancer mouse xenograft model.4
1.Ruiz, F.X., Cousido-Siah, A., Mitschler, A., et al.X-ray structure of the V301L aldo-keto reductase 1B10 complexed with NADP+ and the potent aldose reductase inhibitor fidarestat: Implications for inhibitor binding and selectivityChem. Biol. Interact.202(1-3)178-185(2013) 2.Kato, N., Mizuno, K., Matsubara, A., et al.Effect of long-term treatment with a new aldose reductase inhibitor, (2S,4S)-6-fluoro-2',5'-dioxospiro-[chroman-4,4'-imidazolidine]-2-carbox amide (SNK-860), on peripheral neuropathy in streptozotocin-induced diabetic ratsJ. Diabetes Complications8(1)27-32(1994) 3.Uehara, K., Yamagishi, S., Otsuki, S., et al.Effects of polyol pathway hyperactivity on protein kinase C activity, nociceptive peptide expression, and neuronal structure in dorsal root ganglia in diabetic miceDiabetes53(12)3239-3247(2004) 4.Tammali, R., Reddy, A.B., Saxena, A., et al.Inhibition of aldose reductase prevents colon cancer metastasisCarcinogenesis32(8)1259-1267(2011)