- |||||||||| Kinedak (epalrestat) / Ono Pharma
Journal: Novel determinants of cell size homeostasis in the opportunistic yeast Candida albicans. (Pubmed Central) - Dec 1, 2022
PLoS Genet 15:e1008052, 2019)...Many new size genes of C. albicans were associated with biological processes that were not previously linked to cell size control and offer an opportunity for future investigation. Additional work is needed to understand if mitochondrial activity is a critical element of the metric that dictates cell size in C. albicans and whether modulation of the onset of actomyosin ring constriction is an additional size checkpoint.
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Journal: N-Substituted phthalazine sulfonamide derivatives as non-classical aldose reductase inhibitors. (Pubmed Central) - Nov 5, 2022
Among these agents, 4-(6-nitro-1,4-dioxo-1,2,3,4-tetrahydrophthalazine-2-carbonyl)benzenesulfonamide (5e) and 1,4-dioxo-3-(4-sulfamoylbenzoyl)-1,2,3,4-tetrahydrophthalazine-6-carboxylic acid (5f) showed prominent inhibitory activity with K values of 67.73 and 148.20 nM, respectively, vs AR and were found to be more potent than epalrestat (K = 852.50 nM), the only AR inhibitor currently used in the therapy...According to ADME-Tox, predicts were also determined that these derivatives be ARIs displaying suitable drug-like properties. The sulfonamides identified in this study may be used to develop lead therapeutic agents inhibiting diabetic complications.
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Enrollment open: Oral Epalrestat Therapy in Pediatric Subjects With PMM2-CDG (clinicaltrials.gov) - Oct 27, 2022
P3, N=40, Recruiting,
The sulfonamides identified in this study may be used to develop lead therapeutic agents inhibiting diabetic complications. Not yet recruiting --> Recruiting
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Review, Journal: Strategies in synthetic design and structure-activity relationship studies of novel heterocyclic scaffolds as aldose reductase-2 inhibitors. (Pubmed Central) - Sep 23, 2022
The present study summarizes the recent development (2014 and onwards) of this pharmacologically active ALR2 heterocyclic scaffold and illustrates the rationale behind the design, structure-activity relationships, and biological studies performed on these molecules. The aim of the current review is to pave a straight path for medicinal chemists and chemical biologists, and, in general, to the drug discovery scientists to facilitate the synthesis and development of novel ALR2 inhibitors that may serve as lead molecules for the treatment of diseases related to the ALR2 enzyme.
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Review, Journal: Moving toward a new horizon for the aldose reductase inhibitor epalrestat to treat drug-resistant cancer. (Pubmed Central) - Sep 10, 2022
EPA has revealed a major anticancer effect in an experimental model of basal-like breast cancer and clinical trials have been developed in patients with triple-negative breast cancer. The repurposing of the drug to treat chemo-resistant solid tumors seems promising, but more studies are needed to define the best trajectory for the positioning of EPA in oncology.
- |||||||||| AT-001 / Applied Therap, Kinedak (epalrestat) / Ono Pharma
Journal: CADD Studies in the Discovery of Potential ARI (Aldose Reductase Inhibitors) Agents for the Treatment of Diabetic Complications. (Pubmed Central) - Aug 24, 2022
AR inhibitors (ARI) have been widely discussed in the literature, for example, Epalrestat is currently the only ARI used to treat patients with diabetic neuropathy in Japan, India, and China...AT-001, an AR inhibitor, is now being tested in COVID-19 to see how safe and effective it is at reducing inflammation and cardiac damage...New data shows that diabetes and obesity are among the strongest predictors of COVID-19 hospitalization. Patients and risk factors for severe morbidity and mortality of COVID- 19.
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Journal: Identification of Putative Plant-Based ALR-2 Inhibitors to Treat Diabetic Peripheral Neuropathy. (Pubmed Central) - Jul 26, 2022
Aldose reductase -2 (ALR-2) is an oxidoreductase enzyme that is most extensively studied therapeutic target for diabetes-related complications that can be inhibited by epalrestat, which has severe adverse effects; hence the discovery of potent natural inhibitors is desired...In comparison to the reference drug, four compounds showed increased binding affinity and demonstrated critical residue interactions with greater stability and specificity. As a result, we have identified four potent inhibitors: ZINC000002895847, ZINC000002566593, ZINC000012447255, and ZINC000065074786, that could be used as pharmacological niches to develop novel ALR-2 inhibitors.
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Biomarker, Journal: Comparison of Widely Targeted Metabolomics and Untargeted Metabolomics of Wild Ophiocordyceps sinensis. (Pubmed Central) - Jun 19, 2022
The differentially expressed metabolites identified using the untargeted metabolomics approach were mainly involved in arginine biosynthesis, terpenoid backbone biosynthesis, porphyrin and chlorophyll metabolism, and cysteine and methionine metabolism. The purpose of this research was to provide support for the assessment of the differences between the stroma and sclerotia, to furnish a material basis for the evaluation of the physical effects of OS, and to provide a reference for the selection of detection methods for the metabolomics of OS.
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Journal, IO biomarker: Shabyar Ameliorates High Glucose Induced Retinal Pigment Epithelium Injury Through Suppressing Aldose Reductase and AMPK/mTOR/ULK1 Autophagy Pathway. (Pubmed Central) - May 29, 2022
Human retinal pigment epithelial cells (ARPE-19) induced by high glucose was used as a model in vitro, with Epalrestat (EPL, AR inhibitor) and Difrarel (DFR, DR therapeutic drug) as positive controls...These data demonstrated that SBA treatment inhibits the autophagy of ARPE-19 through the AMPK/mTOR/ULK1 signaling pathway, and reduced early-stage apoptosis occurred by high glucose. These findings reveal the protective role and mechanism of SBA on retinal pigment epithelium, and provide experimental basis for the clinical application of SBA in the treatment of DR.
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Journal: Dual-Loaded Liposomes Tagged with Hyaluronic Acid Have Synergistic Effects in Triple-Negative Breast Cancer. (Pubmed Central) - Apr 23, 2022
These liposomes are biocompatible and effectively target tumor cells owing to hyaluronic acid (HA) modification on their surface. This active targeting, mediated by CD44-HA interaction, allows DOX and EPS to be delivered simultaneously to tumor cells in vivo, where they suppress not only TNBC tumor growth and the epithelial-mesenchymal transition, but also cancer stem cells, which collectively suppress tumor growth and metastasis of TNBC and may also act to prevent relapse of TNBC.
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Journal: 3D culture platform of human iPSCs-derived nociceptors for peripheral nerve modelling and tissue innervation. (Pubmed Central) - Apr 19, 2022
Using this model, we demonstrate that myelin damage can be induced from hyperglycemia exposure (glucose at 45 mM) and mitigated by epalrestat (1µM) supplementation...Finally, as a proof-of-concept, we incorporated pancreatic pseudoislets and endometrial organoids into our nerve platform, to demonstrate the potential in generating nociceptor innervation models. In summary, we propose here an improved tool for neurobiology research with potential applications in pathology modelling, drug screening and target tissue innervation.
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Trial initiation date: Oral Epalrestat Therapy in Pediatric Subjects With PMM2-CDG (clinicaltrials.gov) - Apr 5, 2022
P3, N=40, Not yet recruiting,
This study underscores cognition enhancing abilities of vitamin D and epalrestat, and their combination in diabetic rats with and without scopolamine. Initiation date: Mar 2022 --> Jul 2022
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Journal: Epalrestat suppresses inflammatory response in lipopolysaccharide-stimulated RAW264.7 cells. (Pubmed Central) - Feb 10, 2022
From these results, we propose that targeting the regulation of pro-inflammatory cytokine levels and inflammatory mediators by EPS is a promising therapeutic approach to treat inflammatory injury. It is expected that EPS, whose safety and pharmacokinetics have been confirmed clinically, would be useful for the treatment of inflammatory diseases.
- |||||||||| Kinedak (epalrestat) / Ono Pharma, Qutenza (capsaicin) / Grunenthal, LTS Lohmann Therapy Systems
Review, Journal: Current Concepts in the Management of Diabetic Polyneuropathy. (Pubmed Central) - Feb 1, 2022
In addition to pain relief, therapy should improve sleep, mobility, as well as quality of life. In conclusion, multimodal treatment of DSPN should consider the individual risk profile, pathogenetic treatment, and pain management using pharmacotherapy (combinations, if needed) as well as non-pharmacological options.
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Phase classification, Enrollment change: Oral Epalrestat Therapy in Pediatric Subjects With PMM2-CDG (clinicaltrials.gov) - Jan 20, 2022
P3, N=40, Not yet recruiting,
In conclusion, multimodal treatment of DSPN should consider the individual risk profile, pathogenetic treatment, and pain management using pharmacotherapy (combinations, if needed) as well as non-pharmacological options. Phase classification: P2 --> P3 | N=30 --> 40
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Journal: Biological effects of bis-hydrazone compounds bearing isovanillin moiety on the aldose reductase. (Pubmed Central) - Jan 13, 2022
Moreover, a comprehensive ligand-receptor interactions prediction was performed using ADME-Tox, Glide XP, and MM-GBSA modules of Schrödinger Small-Molecule Drug Discovery Suite to elucidate the novel bis-hydrazone derivatives, potential binding modes versus the ALR2. As a result, these compounds with ALR2 inhibitory effects may be potential alternative agents that can be used to treat or prevent diabetic complications.
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Journal: Combatting Nitrosative Stress and Inflammation with Novel Substituted Triazinoindole Inhibitors of Aldose Reductase in PC12 Cells Exposed to 6-Hydroxydopamine Plus High Glucose. (Pubmed Central) - Dec 16, 2021
The neuroprotective properties of CMTI, COTI, the clinically used epalrestat (EPA), and the pyridoindole antioxidants stobadine and SMe1EC2 were all tested in the neurotoxic models produced by hyperglycemic glucotoxicity (HG, 75 mM D-glucose, 72 h), 6-hydroxydopamine (6-OHDA), and HG+6-OHDA models in PC12 cells...EPA and CMTI also reduced the HG+6-OHDA-induced increase in the cellular levels of nuclear factor kB (NF-KB). The neuroprotective potential of the novel ARIs and the pyridoindole antioxidants studied constitutes a promising tool for the development of therapeutic strategies against DM-induced and PD-related neurodegeneration.
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Biomarker, Journal: Sorbitol is a severity biomarker for PMM2-CDG with therapeutic implications. (Pubmed Central) - Dec 16, 2021
Epalrestat was well-tolerated and led to significant clinical improvements in the first PMM2-CDG pediatric patient treated with epalrestat. We also propose urinary sorbitol as a novel biomarker for disease severity and treatment response in future clinical trials in PMM2-CDG.
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Clinical, Journal: Effects of aldose reductase inhibitors on renal blood flow parameters in patients with early diabetic nephropathy. (Pubmed Central) - Nov 29, 2021
The differential protective effects evoked by the novel ARIs and STB on the toxic models tested herein provide novel and relevant comparative evidence for the design of specific therapeutic strategies against neurodegenerative events associated with neurological disorders. Epalrestat can effectively improve renal arterial blood flow and renal arterial perfusion, which play a protective role in early DN.
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Trial completion date, Trial initiation date, Trial primary completion date: Oral Epalrestat Therapy in Pediatric Subjects With PMM2-CDG (clinicaltrials.gov) - Sep 14, 2021
P2, N=30, Not yet recruiting,
The overall findings of this study suggest that methyl ferulate conjugated prodrugs of epalrestat may be considered as potential protective agents in diabetic neuropathy and nephropathy. Trial completion date: Dec 2025 --> Dec 2026 | Initiation date: Aug 2021 --> Jan 2022 | Trial primary completion date: Dec 2024 --> Dec 2025
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Preclinical, Journal: Identification of a new class of potent aldose reductase inhibitors: Design, microwave-assisted synthesis, in vitro and in silico evaluation of 2-pyrazolines. (Pubmed Central) - Aug 4, 2021
Among these compounds, 1-(3-bromophenyl)-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (20) was identified as the most promising AR inhibitor with an IC value of 0.160 ± 0.005 μM exerting competitive inhibition with a K value of 0.019 ± 0.001 μM as compared to epalrestat (IC = 0.279 ± 0.001 μM; K = 0.801 ± 0.023 μM) and quercetin (IC = 4.120 ± 0.123 μM; K = 6.082 ± 0.272 μM)...Based on in silico pharmacokinetic studies, compound 20 was found to possess favorable oral bioavailability and drug-like properties. It can be concluded that compound 20 is a potential orally bioavailable AR inhibitor for the management of diabetic complications as well as non-diabetic diseases.
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Journal: The Importance of Rhodanine Scaffold in Medicinal Chemistry: A Comprehensive Overview. (Pubmed Central) - Jul 14, 2021
After the clinical use of epalrestat that contains a rhodanine ring, in type II diabetes mellitus and diabetic complications, rhodanin-based compounds have become an important class of heterocyclic in the field of medicinal chemistry...Rhodanine-based compounds will likely stay a privileged scaffold in drug discovery because of different probability of chemical modifications of the rhodanine ring. We have therefore reviewed their biological activities and structure activity relationship.
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Journal: A two-pronged photodynamic nanodrug to prevent metastasis of basal-like breast cancer. (Pubmed Central) - Jun 30, 2021
A two-pronged concept combining photodynamic therapy (PDT) and epithelial-mesenchymal transition (EMT) blockade in a minimalist nanoplatform was proposed to combat basal-like breast cancer (BLBC) metastasis. Based on PDT-mediated tumor killing and epalrestat (Epa)-mediated EMT blockade, as-prepared Ce6/Epa nanoparticles prevented BLBC metastasis effectively in vivo, providing a very promising two-pronged strategy against BLBC metastasis.
- |||||||||| Kinedak (epalrestat) / Ono Pharma
Journal: Sustained delivery of epalrestat to the retina using PEGylated solid lipid nanoparticles laden contact lens. (Pubmed Central) - Jun 22, 2021
In tear fluid (rabbit model) studies, the DL-EP-p-SLN-100 batch showed high epalrestat concentration at all-time points in comparison to the SM-EP-p-SLN-100 batch. The bio-distribution study indicate high epalrestat accumulation in the various ocular tissues including retina, which suggest the potential of p-SLNs laden contact lenses to deliver drug to the posterior side of the eye to treat diabetic eye conditions like cataract and diabetic retinopathy.
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