Novel protein kinase C‐β isoform selective inhibitor JTT‐010 ameliorates both hyper‐ and hypoalgesia in streptozotocin‐ induced diabetic rats

Sasase, Tomohiko; Yamada, Hideki; Sakoda, Kenji; Imagawa, Naoya; Abe, Tetsuya; Ito, Makoto; Sagawa, Shoichi; Tanaka, Masahiro; Matsushita, Mutsuyoshi

doi:10.1111/j.1463-1326.2004.00447.x

Cited by 37 publications

(27 citation statements)

References 47 publications

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“…Ro-32-0432, PKC a inhibitor, was studied for inhibition of oxidative damages in hyperglycemia and effects of these changes in AGE mediated damage in DN in in vitro as well as in in vivo studies. The study demonstrated that JTT-010 ameliorated the reduction in NCV present in diabetic rats [61]. Menne et al [57,58] reported the protection against the development of albuminuria as well as expression of VEGF in knockout mice with PKC a()/)) despite the presence of renal and glomerular hypertrophy.…”

Section: P K C I N H I B I T O R Smentioning

confidence: 92%

Protein kinase C beta inhibitors: a new therapeutic target for diabetic nephropathy and vascular complications

Budhiraja¹,

Singh

2008

Fundamemntal Clinical Pharma

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Diabetic nephropathy (DN) has emerged as the major causative pathology in patients entering end-stage renal disease (ESRD) worldwide and it is responsible for 30-40% of all ESRD cases. Treatments for DN are centered on control of hyperglycemia and blood pressure control. However, current therapeutic regimens have not yet provided satisfactory prevention from the onset of DN. Protein kinase C (PKC) is an intracellular signaling molecule and activation of it plays an important role in the development of diabetic complications. In numerous experimental and clinical studies, inhibition of PKC (LY333531) has been shown to delay/halt the progression of diabetic complications. Presently, the drug is submitted in USA-FDA for new drug application in moderate to severe diabetic retinopathy. This review selectively discusses the role of PKC in DN and therapeutic effects produced by PKC inhibitors in DN. The role of PKC inhibitor in other diabetic complications is also discussed.

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Section: P K C I N H I B I T O R Smentioning

confidence: 92%

Protein kinase C beta inhibitors: a new therapeutic target for diabetic nephropathy and vascular complications

Budhiraja¹,

Singh

2008

Fundamemntal Clinical Pharma

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“…Here, we use 10 inhibitors collected from the literature, for which half-maximal inhibition constants (IC 50 ) values toward PKC isoforms were determined experimentally: corallidictyal 74, GF-109203X 75, Gö-6976 76, JTT-010 77, K252a 78, midostaurin 79, rottlerin 80, ruboxistaurin 81, staurosporine 82 and UCN-01 83. A simple three-state classification model was constructed; for each PKC isoenzyme, the inhibitors were divided into three classes based on the IC 50 values: class I, good binders (IC 50 < 100 nM), class II, weak binders (100nM < IC 50 < 1 μM) and class III, non-binders (IC 50 > 1 μM).…”

Section: Methodsmentioning

confidence: 99%

Comprehensive Structural and Functional Characterization of the Human Kinome by Protein Structure Modeling and Ligand Virtual Screening

Bryliński

Skolnick

2010

J. Chem. Inf. Model.

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The growing interest in the identification of kinase inhibitors, promising therapeutics in the treatment of many diseases, has created a demand for the structural characterization of the entire human kinome. At the outset of the drug development process, the lead-finding stage, approaches that enrich the screening library with bioactive compounds are needed. Here, protein structure-based methods can play an important role, but despite structural genomics efforts, it is unlikely that the three-dimensional structures of the entire kinome will be available soon. Therefore, at the proteome level, structure-based approaches must rely on predicted models, with a key issue being their utility in virtual ligand screening. In this study, we employ the recently developed FINDSITE/Q-Dock Ligand Homology Modeling approach, which is well suited for proteome-scale applications using predicted structures, to provide extensive structural and functional characterization of the human kinome. Specifically, we construct structure models for the human kinome; these are subsequently subject to virtual screening against a library of more than 2 million compounds. To rank the compounds, we employ a hierarchical approach that combines ligand- and structure-based filters. Modeling accuracy is carefully validated using available experimental data with particularly encouraging results found for the ability to identify, without prior knowledge, specific kinase inhibitors. More generally, the modeling procedure results in a large number of predicted molecular interactions between kinases and small ligands that should be of practical use in the development of novel inhibitors. The dataset is freely available to the academic community a user-friendly web interface at http://cssb.biology.gatech.edu/kinomelhm/as well as the ZINC website (http://zinc.docking.org/applications/2010Apr/Brylinski-2010.tar.gz).

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“…are widely employed as rat models of type 2 diabetes mellitus in order to analyze the onset of the disease and to develop antidiabetic agents. In contrast, experimental models treated by alloxan or streptozotocin to induce specific damage to pancreatic b cells are widely used as models of diabetic complications [21]. With these experimental models, though, a direct drug effect on the rat cannot be ruled out and a new spontaneous diabetic rat model is currently desired to analyze diabetic complications.…”

Section: Introductionmentioning

confidence: 99%

Pancreatic Function of Spontaneously Diabetic Torii Rats in Pre-Diabetic Stage

et al. 2009

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Abstract:The Spontaneously Diabetic Torii (SDT) rat is a new model for non-obese type 2 diabetes. In the present study, we investigated changes in insulin secretion from the pancreas of male SDT rats aged 8, 16, and 24 weeks in order to analyze pancreatic function. An analysis of glucose-stimulated insulin secretion (GSIS) in isolated islets showed a marked reduction in insulin secretion in pre-diabetic 16-week-old SDT rats. When the islets were treated with tolbutamide or glucagon-like peptide-1 (7-36) amide (tGLP-1) in the presence of 11.2 mM glucose, however, insulin levels were restored to levels of normal rats. In vivo study, SDT rats exhibited a marked reduction in GSIS from 16 weeks of age. However, tolbutamide or JTP-76209, which is a novel dipeptidyl peptidase IV (DPP IV) inhibitor, increased insulin release after glucose loading and improved glucose tolerance. A marked reduction in GSIS was observed in pre-diabetic SDT rats and the reduction was improved by tolbutamide, tGLP-1, and the DPP IV inhibitor. Therefore, we concluded that the SDT rat is useful, as a model of non-obese insulin secretory disorder, for the analysis of the onset of type 2 diabetes and the development of antidiabetic agents.

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Novel protein kinase C‐β isoform selective inhibitor JTT‐010 ameliorates both hyper‐ and hypoalgesia in streptozotocin‐ induced diabetic rats

Cited by 37 publications

References 47 publications

Protein kinase C beta inhibitors: a new therapeutic target for diabetic nephropathy and vascular complications

Protein kinase C beta inhibitors: a new therapeutic target for diabetic nephropathy and vascular complications

Comprehensive Structural and Functional Characterization of the Human Kinome by Protein Structure Modeling and Ligand Virtual Screening

Pancreatic Function of Spontaneously Diabetic Torii Rats in Pre-Diabetic Stage

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