ranirestat (AS-3201) / Sumitomo Pharma, Eisai - LARVOL DELTA

Structure-Guided Identification and Evaluation of Epalrestat and Ranirestat-Like Compounds Against Aldose Reductase: Therapeutic Management of Diabetic Neuropathy. (PubMed, ChemistryOpen) - "MD simulations supported the stability and preferred dynamics of their interactions with ALDR. These findings suggest that compounds CID:45110135 (N-[3-fluoro-4-(4-fluoro-1,3-dioxoisoindol-2-yl)phenyl]pyridine-2-carboxamide) and CID:58643777 ([(5Z)-4-oxo-2-sulfanylidene-5-[[3-[3-(trifluoromethyl)phenyl]phenyl]methylidene]-1,3-thiazolidin-3-yl]propanoic acid) might have the potential to be lead compounds for the development of new drugs for diabetic neuropathy after required validation."

Journal • Diabetes • Diabetic Neuropathy • Pain • Renal Disease • Retinal Disorders • AKR1B1

Epalrestat Alleviates Reactive Oxygen Species and Endoplasmic Reticulum Stress by Maintaining Glycosylation in IMS32 Schwann Cells Under Exposure to Galactosemic Conditions. (PubMed, Int J Mol Sci) - "Epalrestat and ranirestat did not recover mitochondrial morphology. These findings suggest that ER stress is induced by aberrant glycosylation under galactosemic conditions and that epalrestat may be effective in maintaining proper glycosylation in Schwann cells in these conditions."

Journal • Diabetic Neuropathy • Metabolic Disorders • Pain • AKR1B1

De novo in silico screening of natural products for antidiabetic drug discovery: ADMET profiling, molecular docking, and molecular dynamics simulations. (PubMed, In Silico Pharmacol) - "The compounds had higher binding scores than the standards (acarbose and ranirestat) with ZINC85593620 having the highest docking score of - 12.162 kcal/mol and interacted with key amino acid residues such as TRP 59, ILE 148, and ASP 197. Overall, the compounds displayed potential amylase inhibition which underscores their use as promising natural products in developing new antidiabetic drugs. Further experimental validations are recommended to offer a potential solution to the pressing need for safer and more effective antidiabetic therapies."

Journal • Diabetes • Metabolic Disorders

In vitro evaluation of the reductive carbonyl idarubicin metabolism to evaluate inhibitors of the formation of cardiotoxic idarubicinol via carbonyl and aldo-keto reductases. (PubMed, Arch Toxicol) - "Over-expression of AKR1C3 verified the importance of AKR1C3 for idarubicinol formation and showed that ranirestat is also a potent inhibitor of this enzyme. Taken together, our study underlines the importance of AKR1C3 and CBR1 for the reduction of idarubicin and identifies potent inhibitors of metabolic formation of the cardiotoxic idarubicinol, which should now be tested in vivo to evaluate whether such combinations can increase the cardiac safety of idarubicin therapies while preserving its efficacy."

Journal • Preclinical • Cardiovascular • AKR1B1 • AKR1C3

Cheminformatics identification of modulators of key carbohydrate-metabolizing enzymes from C. cujete for type-2 diabetes mellitus intervention. (PubMed, J Diabetes Metab Disord) - "The MD simulation results revealed compounds such as benzoic acid (-48.414 kcal/mol) and phytol (-45.112 kcal/mol) as well as chlorogenic acid (-42.978 kcal/mol) and naringenin (-31.292 kcal/mol) had higher binding affinities than the standards [acarbose (-28.248 kcal/mol), ranirestat (-21.042 kcal/mol)] against alpha-glucosidase and aldose reductase, respectively while Diprotin A (-45.112 kcal/mol) and ursolic acid (-18.740 kcal/mol) presented superior binding affinities than the compounds [luteolin (-41.957 kcal/mol and naringenin (-16.518 kcal/mol)] against DPP-IV and PTP-1B respectively. Further studies are warranted in vitro and in vivo on the antihyperglycaemic effects of these drug candidates. The online version contains supplementary material available at 10.1007/s40200-023-01249-7."

Journal • Diabetes • Metabolic Disorders • Retinal Disorders • Type 2 Diabetes Mellitus • AKR1B1 • PTPN1

Ranirestat Improves Electrophysiologic but not Clinical Measures of Diabetic Polyneuropathy: A Meta-Analysis. (PubMed, Indian J Endocrinol Metab) - "Treatment-emergent adverse events [risk ratio (RR) 0.85 (95%CI: 0.63-1.14); P = 0.28; I = 0%] and severe adverse events [RR 1.35 (95%CI: 0.86-2.11); P = 0.20; I = 0%] were comparable across study groups. In people with established DPN with long-standing diabetes, ranirestat is safe and effective in improving electrophysiologic but not clinical DPN."

Journal • Retrospective data • Review • Diabetes • Diabetic Neuropathy • Metabolic Disorders • Pain • AKR1B1

Ranirestat Improved Nerve Conduction Velocities, Sensory Perception, and Intraepidermal Nerve Fiber Density in Rats with Overt Diabetic Polyneuropathy. (PubMed, J Diabetes Res) - "Twelve weeks after the onset of diabetes, rats which had an established polyneuropathy were treated once daily with a placebo, ranirestat, or epalrestat, over 6 weeks. Ranirestat improved the peripheral nervous dysfunctions in rats with advanced diabetic polyneuropathy. Ranirestat could have potential for regeneration in the peripheral nervous system of diabetic rats."

Journal • Preclinical • CNS Disorders • Diabetic Neuropathy • Gene Therapies • Metabolic Disorders • Pain

Pharmacokinetics and Safety of Ranirestat in Patients With Hepatic Impairment. (PubMed, J Clin Pharmacol) - "All adverse events were mild in severity. Based on these findings, no dose adjustment will be required for ranirestat in patients with mild or moderate hepatic impairment."

Clinical • Journal • PK/PD data • Diabetes • Diabetic Neuropathy • Gene Therapies • Metabolic Disorders • Pain • AKR1B1

A novel method of producing the key intermediate ASI-2 of ranirestat using a porcine liver esterase (PLE) substitute enzyme. (PubMed, Biosci Biotechnol Biochem) - "A novel esterase EstBT that produces Z-MME-AE was purified from Bacillus thuringiensis NBRC13866 and was stably produced in Escherichia coli JM109 cells. Using EstBT rather than porcine liver esterase (PLE), ASI-2 was synthesized with a 17% higher total yield by a novel method, suggesting that the esterase EstBT is a PLE substitute enzyme and therefore, may be of interest for future industrial applications."

Journal • Preclinical

Aldose reductase inhibitor ranirestat significantly improves nerve conduction velocity in diabetic polyneuropathy: a randomized double-blind placebo-controlled study in Japan. (PubMed, J Diabetes Investig) - "Ranirestat (40 mg/day) was well tolerated and improved nerve conduction velocity. Regarding symptoms and signs, no detectable benefits over the placebo were observed in the ranirestat group during the 52 weeks of treatment."

Clinical • Journal