Kinedak (epalrestat) / Ono Pharma - LARVOL DELTA

Targeting aldose reductase in pulmonary fibrosis: Blocking de novo fatty acid synthesis halts pro-fibrotic M2 polarization. (PubMed, Int J Biol Macromol) - "Here, we observed elevated AR expression and activity in the serum of patients with IPF and in the lungs of mice and rats with bleomycin - induced pulmonary fibrosis. Our findings indicate that AR plays a crucial role in pulmonary fibrosis by activating ERK-MYC signaling, promoting the expression of FASN and ACC1, enhancing fatty acid synthesis, and inducing macrophage M2 polarization. Notably, Epalrestat-an aldose reductase inhibitor approved by the Food and Drug Administration (FDA) for the treatment of diabetic neuropathy-exhibits potent antifibrotic effects in preclinical models, which supports its immediate clinical applicability for the repurposing of IPF treatment."

Journal • Diabetes • Diabetic Neuropathy • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Metabolic Disorders • Oncology • Pain • Pulmonary Disease • Respiratory Diseases • ACACA • AKR1B1 • FAS • FASN • IL4

A comparative study to assess two doses of a novel aldose reductase inhibitor (ARI)/Antioxidant drug candidate Cemtirestat, the current ARI drug Epalrestat, and the antioxidant Stobadine on Fructose- and Streptozotocin-Induced hepatic and pancreatic stress responses in rats. (PubMed, J Diabetes Metab Disord) - "The findings may offer valuable insights that could facilitate the development of novel ARI/AO compounds and CMTI derivatives. The online version contains supplementary material available at 10.1007/s40200-025-01723-4."

Journal • Preclinical • Diabetes • Metabolic Disorders • AKR1B1 • CASP3 • CAT • PCNA

Synthesis of new Pyridazinone derivatives and their dual inhibitory activity on aldose reductase and α-glucosidase. (PubMed, Bioorg Med Chem Lett) - "Among the tested molecules, compound 4, bearing a fluorinated thiadiazole moiety, exhibited the most potent activity with Ki values of 0.094 μM (ALR2) and 0.171 μM (α-Glu), surpassing standard inhibitors epalrestat and acarbose, respectively. These findings suggest that halogenated pyridazinone derivatives, especially fluorinated thiadiazole analogs, represent promising dual inhibitors for managing hyperglycemia and preventing diabetic complications. The dual-targeting approach demonstrated in this work offers a rational design framework for future antidiabetic drug development."

Journal • Diabetes • Metabolic Disorders • Pain • Renal Disease • Retinal Disorders • AKR1B1

C-5-Arylidene-Thiazolidine-2,4-Dione Analogs Against Aldose Reductase: Design, Synthesis, Biological Evaluation, and Computational Insights. (PubMed, Arch Pharm (Weinheim)) - "Among them, compounds 9h and 9a exhibited superior potency against aldose reductase protein with IC50 values of 0.98 and 1.05 µM, respectively, as compared with the reference drug epalrestat (IC50 value of 1.20 µM)...Predicted in silico toxicity data suggested that the synthesized compounds were inactive and nontoxic against peroxisome proliferator-activated receptor-γ protein. These finding results support the potential of thiazolidine-2,4-dione derivatives as promising AR inhibitors for managing diabetic complications."

Journal • Diabetes • Metabolic Disorders • AKR1B1

Targeting the polyol pathway in NSCLC: Trans-(±)-kusunokinin demonstrates anti-migratory and survival benefits in in vitro and in vivo models. (PubMed, Biomed Pharmacother) - "Remarkably, KU suppressed AKR1B1 and SORD expression, reduced intracellular sorbitol and fructose levels, and induced alterations in EMT-related proteins, such as ZEB1, E-cadherin, and vimentin, at a lower concentration than epalrestat (EP), a known AKR1B1 inhibitor...Collectively, these findings suggest that KU inhibits the aggressive phenotype of lung cancer by targeting the polyol pathway and modulating EMT processes. These results support its potential as a therapeutic candidate, highlighting the need for clinical evaluation in NSCLC patients."

Journal • Preclinical • Diabetes • Lung Cancer • Metabolic Disorders • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AKR1B1 • CDH1 • KRAS • STK11 • VIM • ZEB1

Fostering Collaborative Care in Multiple Myeloma: An Update on the Impact of Holistic Education on Decision-Making with Antibody and CAR-T Platforms (ASH 2024) - "ABSTRACT e21008)...In a meta-analysis of outcomes from the 9 activities, learning objectives were grouped by key themes, with changes in knowledge and skills averaged across them.Results : Total learners : 13,260 (including hematologist-oncologists/oncologists : 8,179; oncology nurses : 1,296). In all activities, learners' knowledge and skills improved, with increases of : 35 percentage points (ppt) in knowledge of new evidence and changing practice guidelines supporting BCMA antibody platforms in RRMM (45% to 80%); 36 ppt in skills in treatment planning and evidence-based integration of CD38 and BCMA-targeting antibodies in the management of MM (52% to 88%); 54 ppt in ability to address safety considerations related to the use of antibody therapy and BCMA immunotherapy (32% to 86%); and 58 ppt in patient interaction skills (eg, counseling, shared decision-making) when using antibody-based and CAR-T platforms (28% to 86%).Conclusions : Improvements in knowledge and..."

Hematological Malignancies • Multiple Myeloma • Oncology

Study on the efficacy and safety of Xuezhikang capsule combination with epalrestaton in treating diabetic peripheral neuropathy patients. (PubMed, Medicine (Baltimore)) - "The level was lower than before treatment and the control group, while the level of high-density lipoprotein was higher than before treatment and the control group, with a statistically significant difference (P < .05); after treatment, the Toronto Clinical Scoring System scores of both groups were lower than before treatment, and the treatment group was lower than the control group, with a statistically significant difference; after treatment, the motor conduction velocity of the median nerve and common peroneal nerve, as well as the sensory conduction velocity of the sural nerve, median nerve, and common peroneal nerve in both groups were higher than before treatment, and the treatment group was higher than the control group, with statistical significance (P < .05); logistic regression analysis showed that high HbA1c, high triglycerides, high C-reactive protein, low high-density lipoprotein, and course of disease were risk factors for diabetes peripheral..."

Journal • Retrospective data • Diabetes • Diabetic Neuropathy • Dyslipidemia • Hypertriglyceridemia • Metabolic Disorders • Oncology • Pain • Type 2 Diabetes Mellitus • CRP

Rhodanine-Sulfonate hybrids targeting aldose reductase: Synthesis, in vitro inhibition, molecular docking, and cytotoxicity studies. (PubMed, Mol Divers) - "In vitro enzyme inhibition assays revealed that all compounds acted as competitive inhibitors, with several analogues, particularly compounds 6 and 8, exhibiting stronger ALR2 inhibition (Ki = 0.43 µM and 0.48 µM, respectively) than the reference drug epalrestat (Ki = 0.98 µM)...Cytotoxicity studies on L929, A549, and RG-2 cell lines revealed that most compounds were less toxic than the reference drug at lower concentrations, with compound 8 showing a promising cytotoxic profile. These findings position rhodanine-sulfonate hybrids as promising scaffolds for the development of next-generation ALR2 inhibitors for the treatment of diabetic complications."

Journal • Preclinical • Diabetes • AKR1B1

Iparomlimab and Tuvonralimab combined with irinotecan liposome is used in recurrent/metastatic nasopharyngeal carcinoma after anti-PD - (L) 1 monoclonal antibody treatment (ChiCTR) - P2 | N=36 | Not yet recruiting | Sponsor: Chongqing University Cancer Hospital; Chongqing University Cancer Hospital

New P2 trial • Head and Neck Cancer • Nasopharyngeal Carcinoma • Oncology • Solid Tumor

Exploring the efficacy and safety of famitinib combined with epalrestat and torivirine in the treatment of advanced and recurrent/metastatic cervical cancer (ChiCTR) - P2 | N=90 | Not yet recruiting | Sponsor: Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine; Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of

New P2 trial • Cervical Cancer • Oncology • Solid Tumor • PD-L1

The role of chikungunya virus capsid-viral RNA interactions in programmed ribosomal frameshifting. (PubMed, J Virol) - "Carey, I. Akhrymuk, B. Dahal, C. L. Pinkham, et al., PLOS Pathogens 16:e1008282, 2020, https://doi.org/10.1371/journal.ppat.1008282), suggesting that capsid-mediated modulation of translation may represent a partially conserved mechanism across the alphavirus genus. By elucidating a role for capsid in PRF modulation, this study highlights a previously unrecognized layer of gene regulation in alphaviruses with broad implications for immune evasion, viral fitness, and translational control."

Journal • Chikungunya • CNS Disorders • Immunology • Infectious Disease • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Pain • Rheumatology

Oral Epalrestat Therapy in Pediatric Subjects With PMM2-CDG (clinicaltrials.gov) - P3 | N=42 | Terminated | Sponsor: Maggie's Pearl, LLC | Trial completion date: Dec 2025 ➔ Feb 2025 | Active, not recruiting ➔ Terminated; Due to futility

Trial completion date • Trial termination • Pediatrics • PMM2

Comparative efficacy of moxibustion as an add-on treatment with different durations for diabetic peripheral neuropathy: study protocol for a randomized controlled trial. (PubMed, Front Neurol) - P=N/A | "The conventional treatment group will be administered mecobalamin and epalrestat for a duration of 4 weeks, while the moxibustion groups will receive moxubustion as an add-on therapy treatment twice a week over the same period...The findings could enhance treatment efficacy, reduce adverse effects, and alleviate DPN's socio-economic burden. https://clinicaltrials.gov/, NCT06330233."

Journal • Diabetic Neuropathy • Pain • Peripheral Neuropathic Pain

Development and Exploration of Organic Compounds as Aldose Reductase Inhibitors: An Overview. (PubMed, Curr Top Med Chem) - "These include: i) derivatives of carboxylic acids (e.g., Epalrestat, Alrestatin, Zopalrestat, Zenarestat, Ponalrestat, Lidorestat, and Tolrestat); ii) derivatives of spirohydantoins and related cyclic amides (e.g., Sorbinil, Minalrestat, and Fidarestat); and iii) phenolic derivatives (e.g., related to Benzopyran- 4-one and Chalcone). This also describes the advancements made in ARI research and possible applications by obtaining the required data. The process involves thoroughly searching multiple databases-such as PubMed, ScienceDirect, and SciFinder-for citations."

Journal • Cardiovascular • Cataract • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Ophthalmology • Renal Disease • Retinal Disorders • AKR1B1

Optimized synthesis of 5N-D and the exploration of its role as a promising anti-aging agent via AKR1B1 inhibition and PI3K/Akt/Nrf2 regulation. (PubMed, Bioorg Chem) - "All these indexes are far better than the positive Epalrestat (EPA)...5 N-D prolongs lifespan of C. elegans via the regulation of stress response genes such as PMK-1, DAF-16, AGE-1, AKT-1, AGE-1, SIR-2.1, and SKN-1. The results consistently support the potential of 5 N-D as an anti-aging agent."

Journal • Diabetes • AKR1B1 • CAT

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

Molecular and structural characterization of ureido-benzenesulfonamides as dual inhibitors of aldose reductase and cholinesterases. (PubMed, Arch Biochem Biophys) - "Spectrophotometric inhibition assays revealed that compound 3SA-a displayed exceptional ALR2 affinity (KI = 7.00 ± 0.68 nM), surpassing epalrestat by over 30-fold. Likewise, 3SA-f selectively inhibited BChE with a KI of 24.20 ± 2.26 nM, outperforming tacrine by a factor of 7.8...Complementary in silico ADME-Tox predictions confirmed the drug-like nature of all compounds (0 Lipinski/PAINS violations), moderate oral permeability (QPPCaco: 79-85 nm/s), and low CNS exposure (CNS score = -2), aligning with a peripheral mechanism of action. Collectively, this study provides a detailed structural and dynamic framework for dual-target enzyme inhibition, offering a tunable scaffold for future therapeutics targeting the ALR2-ChE axis."

Journal • CNS Disorders • Pain • AKR1B1

Chalcone-inspired indole, carbazole, and phenothiazine hybrids as potent aldose reductase inhibitors with selective anticancer potential: Rational design, synthesis, and multi-level characterization. (PubMed, Bioorg Chem) - "Enzymatic inhibition assays revealed low-nanomolar to low-nanomolar KI values, with compound 8b (KI = 3.59 nM, pKI = 8.44) emerging as the most potent inhibitor, outperforming the reference drug Epalrestat...Molecular dynamics simulations confirmed binding stability, while target prediction analyses suggested low off-target risk. This multi-parametric evaluation underscores the translational potential of scaffold-tuned ALR2 inhibitors as oxidative stress-modulating agents with cancer-selective properties."

Journal • Diabetes • Hepatocellular Cancer • Liver Cancer • Lung Cancer • Oncology • Solid Tumor • AKR1B1

Targeting AKR1B1 inhibits metabolic reprogramming to reverse systemic therapy resistance in hepatocellular carcinoma. (PubMed, Signal Transduct Target Ther) - "In terms of overcoming resistance, the AKR1B1 inhibitor epalrestat significantly mitigated drug resistance when it was used in combination with standard therapies. These findings underscore the importance of metabolic reprogramming in the development of HCC resistance. AKR1B1, a key enzyme that regulates metabolic reprogramming, has been identified as a potential biomarker and therapeutic target, providing new insights into overcoming resistance in HCC treatment."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • AKR1B1

N-substituted phthalimide-carboxylic acid hybrids as dual-targeted aldose reductase inhibitors: Synthesis, mechanistic insights, and cancer-relevant profiling. (PubMed, Bioorg Chem) - "Among the series, compound 5f demonstrated the highest inhibitory potency (KI = 7.34 nM), outperforming epalrestat (KI = 232.1 nM)...Transcriptomic data from CCLE and DepMap confirmed AKR1B1 overexpression in these cancer models. Network analysis linked ALR2 to redox imbalance and inflammation, suggesting its broader role in tumorigenesis."

Journal • Diabetes • Inflammatory Arthritis • Lung Cancer • Oncology • Solid Tumor • AKR1B1

Effects of High Glucose on Simulated Ischemia/Reperfusion Injury in Isolated Cardiomyocytes. (PubMed, Int J Mol Sci) - "These findings suggest that high glucose exacerbates IR injury in cardiomyocytes, with the polyol pathway playing a critical role. Targeting this pathway with AR inhibitors like Epalrestat may offer a protective strategy against diabetic heart complications."

Journal • Cardiovascular • Diabetes • Metabolic Disorders • Reperfusion Injury • Type 2 Diabetes Mellitus • AKR1B1

Targeted Inhibition of Aldose Reductase by Isoliquiritigenin Suppresses Fatty Acid Synthesis to Inhibit Macrophage M2 Polarization and Alleviate Pulmonary Fibrosis. (PubMed, J Agric Food Chem) - "This study demonstrates that ISL mitigates bleomycin-induced pulmonary fibrosis and macrophage M2 polarization...AR knockdown and AR inhibitor epalrestat suppressed the ERK-MYC signaling pathway, FAS, and macrophage M2 polarization...Collectively, these findings suggest that ISL inhibits FAS, thereby suppressing macrophage M2 polarization and improving pulmonary fibrosis through modulation of the ERK signaling pathway by targeting AR. ISL may be a potentially effective medicine and food additive for the treatment of pulmonary fibrosis."

Journal • Immunology • Pulmonary Disease • Respiratory Diseases • AKR1B1

Molecular docking analysis of aldose reductase with herbal compounds from selected siddha medicine for anti-cataract treatment. (PubMed, Bioinformation) - "Analysis shows that berberine, piperine, sesamin and carinol have optimal binding interactions with aldose reductase, performing similar to the standard drug epalrestat having estimated free energy values of -10.37 kcal/mol and -10.13 kcal/mol, respectively for further consideration. Thus, the traditional use of these herbs in Siddha medicine as a potential, affordable and non-surgical cataract-preventative agent is shown."

Journal • Cataract • Ophthalmology • AKR1B1

Antidiabetic Properties of Dihydrooxazole Derivatives: In Vitro and In Silico Evaluation as Potential Aldose Reductase and α-Glucosidase Inhibitors. (PubMed, Arch Biochem Biophys) - "The experimental inhibitory effect towards aldose reductase (ALR2) and α-glucosidase (α-Glu) was followed, with some of the compounds showing higher activity than standard compounds, epalrestat, and acarbose. The interactions at the molecular level were investigated by molecular docking simulation, and the specific binding explained the relative reactivity order. The toxicity of compounds was assessed through ecotoxicology examination."

Journal • Preclinical • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • AKR1B1

Epalrestat, an aldose reductase inhibitor, mitigates doxorubicin-induced cardiotoxicity by inhibiting glycometabolism. (PubMed, Int Immunopharmacol) - "EPS is a promising pharmacological agent for protection against DOX-induced cardiotoxicity due to its antioxidative and antiapoptotic effects and its ability to inhibit AGE/RAGE/NF-κB signaling."

IO biomarker • Journal • Cardiovascular • Metabolic Disorders • AKR1B1 • BAX • BCL2 • CASP3 • NPPB