Yuhan Research Institute

Gyeonggi do, South Korea

Yuhan Research Institute

Gyeonggi do, South Korea
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Oh Y.S.,Gachon University | Oh Y.S.,Gil Hospital | Lee Y.-J.,Gachon University | Park K.,Yuhan Research Institute | And 4 more authors.
European Journal of Pharmaceutical Sciences | Year: 2014

Glucokinase (GK), an enzyme that phosphorylates glucose to form glucose-6-phosphate, has a role in regulating insulin secretion and proliferation in beta cells. GK activators (GKAs) have been developed as new therapies for type 2 diabetes. In this study, we evaluated the proliferation and anti-apoptotic actions of YH-GKA, a novel and potent GKA, in INS-1 pancreatic β-cells. YH-GKA treatment increased cell numbers at 3 mM glucose via upregulation of insulin receptor substrate-2 and subsequent activation of AKT/protein kinase B phosphorylation. YH-GKA also increased beta-catenin and cyclin D2 mRNA expression and inactivated GSK3β by increasing phosphorylation. These proliferative effects of YH-GKA were attenuated by IRS-2 downregulation. Moreover, YH-GKA reduced annexin-V-stained cells and expression levels of cleaved poly (ADP-ribose) polymerase and caspase-3 induced by glucotoxicity. YH-GKA inhibited apoptotic signaling via induction of ATP content, mitochondrial membrane potential, and citrate synthase activity and was correlated with changes of the mitochondrial function-related genes. YH-GKA also increased interaction between GK and voltage-dependent anion-selective channel protein. Our results suggest that the novel GKA, YH-GKA, promotes beta cell growth and prevents glucotoxic beta cell apoptosis. Therefore, YH-GKA may provide a therapy that compensates for beta cell loss in patients with type 2 diabetes. © 2013 Published by Elsevier B.V.


Seo H.-S.,Yuhan Research Institute | Roh D.-H.,Seoul National University | Kwon S.-G.,Seoul National University | Yoon S.-Y.,University of Houston | And 5 more authors.
Neuropharmacology | Year: 2011

Peripheral ischemia is commonly associated with an increase in tissue ATP concentration and a decrease in tissue pH. Although in vitro data suggest that low tissue pH can affect ATP-binding affinities to P2 receptors, the mechanistic relationship between ATP and low pH on peripheral nociception has not been fully examined. This study was designed to investigate the potential role of an acidified environment on intraplantar αβmeATP-induced peripheral pain responses in rats. The mechanical allodynia (MA) produced by injection of αβmeATP was significantly increased in animals that received the drug diluted in pH 4.0 saline compared to those that received the drug diluted in pH 7.0 saline. Moreover, animals injected with αβmeATP (100 nmol) in pH 4.0 saline developed thermal hyperalgesia (TH), which did not occur in animals treated with αβmeATP diluted in pH 7.0 saline. To elucidate which receptors were involved in this pH-related facilitation of αβmeATP- induced MA and TH, rats were pretreated with PPADS (P2 antagonist), TNP-ATP (P2X antagonist), MRS2179 (P2Y1 antagonist), AMG9810 (TRPV1 antagonist) or amiloride (ASIC blocker). Both PPADS and TNP-ATP dose-dependently blocked pH-facilitated MA, while TH was significantly reduced by pre-treatment with MRS2179 or AMG9810. Moreover, amiloride injection significantly reduced low pH-induced facilitation of αβmeATP-mediated MA, but not TH. These results demonstrate that low tissue pH facilitates ATP-mediated MA via the activation of P2X receptors and ASICs, whereas TH induced by ATP under low pH conditions is mediated by the P2Y1 receptor and TRPV1, but not ASIC. Thus distinct mechanisms are responsible for the development of MA and TH under conditions of tissue acidosis and increased ATP. © 2010 Elsevier Ltd. All rights reserved.


Mahat B.,Chungnam National University | Chae J.-W.,Chungnam National University | Baek I.-H.,Yuhan Research Institute | Song G.-Y.,Chungnam National University | And 3 more authors.
Biological and Pharmaceutical Bulletin | Year: 2012

Angelica gigas NAKAI is used to treat dysmenorrhea, amenorrhea, menopause, abdominal pain, injuries, migraine, and arthritis. The present study provided a physicochemical and toxicological characterization of compounds in A. gigas NAKAI (decursin, decursinol angelate, diketone decursin, ether decursin, epoxide decursin and oxim decursin). Diketone decursin (173.16 μg/mL) and epoxide decursin (122.12 μg/mL) exhibited >100 μg/mL kinetic solubility after applying nephelometry, suggesting a highly soluble compound. The Student's t-test revealed significant differences in the pKa ranges of the compounds by automatic titration from capillary electrophoresis (p<0.05). Diketone decursin, epoxide decursin and oxim decursin might be formulated into an oral dosage form (log P: 0-3) by an automatic titration analysis. A parallel artificial membrane permeability assay demonstrated permeability coefficients of <10-×10--6 cm/s for all of the compounds, suggesting poor permeability. Ether decursin exhibited a toxic effect after being applied to mouse (NIH 3T3, EC50: 57.9 μM) and human (HT-29, EC50: 36.1 μM; Hep-G2, EC50: 4.92 μM) cells. Additionally, epoxide and oxim decursin were toxic through acute oral toxicity (four and three deaths of Institute of Cancer Research (ICR) mice) and mutation toxicity testing by applying Salmonella typhimurium cells with and without S9. Although diketone decursin exhibited less permeability, it is potentially valuable pharmacological compound that should be investigated. © 2012 The Pharmaceutical Society of Japan.


Baek I.-H.,Chungnam National University | Baek I.-H.,Yuhan Research Institute | Lee B.-Y.,Chungnam National University | Kim M.-S.,Inje University | Kwon K.-I.,Chungnam National University
European Journal of Drug Metabolism and Pharmacokinetics | Year: 2013

Doxifluridine (5′-deoxy-5-fluorouridine, 5′-dFUR) is a fluoropyrimidine derivative that is activated preferentially in malignant cells by thymidine phosphorylase to form 5-fluorouracil (5-FU). The purpose of this study was to investigate the pharmacokinetic properties of doxifluridine and its two major metabolites, 5-FU, and 5-fluorouridine (5-FUrd), in beagle dogs following a single oral administration of 200 mg doxifluridine capsule (Furtulon®). After the administration of 200 mg of Furtulon to 23 beagle dogs, the plasma concentrations of doxifluridine, 5-FU, and 5-FUrd were measured simultaneously, using LC-MS/MS. The parent-metabolite compartment model with first-order absorption and Michaelis-Menten kinetics described the pharmacokinetics of doxifluridine, 5-FU, and 5-FUrd. Michaelis-Menten kinetics sufficiently explained the generation and elimination processes of 5-FU and 5-FUrd. The studies described here are the first to evaluate the relationship between pharmacokinetics of doxifluridine and its metabolites in dogs, and these findings will help in understanding the toxicity mechanism of doxifluridine. © 2013 Springer-Verlag France.


Chae J.-W.,Chungnam National University | Baek I.-H.,Yuhan Research Institute | Lee B.-Y.,Chungnam National University | Cho S.-K.,Samnam Pharmaceuticals | Kwon K.-I.,Chungnam National University
British Journal of Clinical Pharmacology | Year: 2012

AIMS To develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model for metformin (500mg) using the signal transduction model in healthy humans and to predict the PK/PD profile in patients with type 2 diabetes. METHODS Following the oral administration of 500mg metformin to healthy humans, plasma concentrations of metformin were measured using LC-MS/MS. A sequential modelling approach using NONMEM VI was used to facilitate data analysis. Monte Carlo simulation was performed to predict the antihyperglycaemic effect in patients with type 2 diabetes. RESULTS Forty-two healthy humans were included in the study. Population mean estimates (relative standard error, RSE) of apparent clearance, apparent volume of distribution and the absorption rate constant were 52.6lh-1 (4.18%), 113l (56.6%) and 0.41h-1, respectively. Covariate analyses revealed that creatinine clearance (CLCR) significantly influenced metformin: CL/F= 52.6 × (CLcr/106.5)0.782. The signal transduction model was applied to describe the antihyperglycaemic effect of metformin. The population means for efficacy, potency, transit time and the Hill coefficient were estimated to be 19.8 (3.17%), 3.68μgml-1 (3.89%), 0.5h (2.89%) and 0.547 (9.05%), respectively. The developed model was used to predict the antihyperglycaemic effect in patients with type 2 diabetes. The predicted plasma glucose concentration value was similar to previous values. CONCLUSIONS The population signal transduction model was developed and evaluated for metformin use in healthy volunteers. Model evaluation by non-parametric bootstrap analysis suggested that the proposed model was robust and parameter values were estimated with good precision. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.


Lee B.-Y.,Chungnam National University | Yoon H.-K.,Korea Food and Drug Administration | Baek I.-H.,Yuhan Research Institute | Kwon K.-I.,Chungnam National University
Alcohol | Year: 2013

The objective of this study was to determine population-based pharmacokinetics parameters for ethanol following multiple intake and to identify the factors influencing the pharmacokinetics. Three different solutions of alcoholic liquor (ethanol 55.39 ± 0.45 g) with different dissolved oxygen concentrations were administered, and blood alcohol concentration was determined in 59 healthy subjects using a breath analyzer. Samples (n = 2955) were collected at various time points. Population pharmacokinetic modeling was performed to describe the pharmacokinetics of ethanol. The influence of individuals' demography and dissolved oxygen concentration was investigated, and Visual Predictive Check and bootstrapping were conducted for internal evaluation. The developed model was used to perform simulations to visualize the effects of covariates on individuals. A one-compartment model with Michaelis-Menten elimination kinetics described the multiple ethanol intake data. Population pharmacokinetic estimates of Vmax and Km were 3.256 mmol min-1 and 0.8183 mmol L-1, respectively. Vd/F was estimated to be 77.0 L, and Ka was 0.0767 min-1. Body weight, age, and the dissolved oxygen concentration were confirmed to be significant covariates. The mean estimates from the developed population pharmacokinetic model were very similar to those from 500 bootstrap samples, and Visual Predictive Check showed that approximately 94% of the observed data fit well within the 5th-95th percentile. A one-compartment model with nonlinear elimination kinetics for multiple ethanol intake was developed and the significant covariates were determined. The robustness of the developed model was evaluated by bootstrap and Visual Predictive Check. The final model and implanted covariates explained well the variability and underlying mechanism of ethanol PK. © 2013 Elsevier Inc.


Yoon Y.A.,Yuhan Research Institute | Park C.S.,Yuhan Research Institute | Cha M.H.,Yuhan Research Institute | Choi H.,Yuhan Research Institute | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

A series of pyrimidine derivatives as acid pump antagonists (APAs) was synthesized and the inhibitory activities against H+/K+ ATPase isolated from hog gastric mucosa were determined. After elaborating on substituents at C2 and C4 position of the pyrimidine scaffold, we have observed that the compound 7h is a potent APA with H+/K+ ATPase, IC50 = 52 nM. © 2010 Elsevier Ltd. All rights reserved.


Park K.,Yuhan Research Institute | Lee B.M.,Yuhan Research Institute | Kim Y.H.,Yuhan Research Institute | Han T.,Yuhan Research Institute | And 5 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

Novel benzamide derivatives were synthesized and tested at in vitro assay by measuring fold increase of glucokinase activity at 5.0 mM glucose concentration. Among the prepared compounds, YH-GKA was found to be an active glucokinase activator with EC50 of 70 nM. YH-GKA showed similar glucose AUC reduction of 29.6% (50 mg/kg) in an OGTT study with C57BL/J6 mice compared to 29.9% for metformin (300 mg/kg). Acute treatment of the compound in C57BL/J6 and ob/ob mice elicited basal glucose lowering activity. In subchronic study with ob/ob mice, YH-GKA showed significant decrease in blood glucose levels and no adverse effects on serum lipids or body weight. In addition, YH-GKA exhibited high bioavailability and moderate elimination in preclinical species. © 2012 Elsevier Ltd. All rights reserved.


Park K.,Yuhan Research Institute | Lee B.M.,Yuhan Research Institute | Hyun K.H.,Yuhan Research Institute | Lee D.H.,Yuhan Research Institute | And 5 more authors.
Bioorganic and Medicinal Chemistry | Year: 2014

Novel heteroaryl-containing benzamide derivatives were synthesized and screened using an in vitro assay measuring increases in glucose uptake and glucokinase activity stimulated by 10 mM glucose in rat hepatocytes. From a library of synthesized compounds, 3-(4-methanesulfonylphenoxy)-N-[1-(2-methoxy- ethoxymethyl)-1H-pyrazol-3-yl]-5-(3-methyl pyridin-2-yl)-benzamide (19e) was identified as a potent glucokinase activator with assays demonstrating an EC50 of 315 nM and the induction of a 2.23 fold increase in glucose uptake. Compound 19e exhibited a glucose AUC reduction of 32% (50 mg/kg) in an OGTT study with C57BL/6J mice compared to 28% for metformin (300 mg/kg). Single treatment of the compound in C57BL/J6 and ob/ob mice elicited basal glucose lowering activity, while in a two-week repeated dose study with ob/ob mice, the compound significantly decreased blood glucose levels with no evidence of hypoglycemia risk. In addition, 19e exhibited favorable pharmacokinetic parameters in mice and rats and excellent safety margins in liver and testicular toxicity studies. Compound 19e was therefore selected as a development candidate for the potential treatment of type 2 diabetes. © 2014 Elsevier Ltd. All rights reserved.


Glucokinase activator is expectedly associated with a dual mechanism for lowering blood glucose concentration by the enhancement of glucose uptake in the liver and insulin secretion from pancreatic beta cell. Therefore, glucokinase has been an attractive target for anti-diabetic therapy. Novel benzamide derivatives were synthesized and tested using in vitro assays by measuring fold increase of glucokinase activity at 5.0 mM glucose concentration. Among the prepared compounds, YH-GKA was found to be an active glucokinase activator with EC50 of 70 nM and glucose area under the curve reduction of 29.6% at 50 mg/kg in an oral glucose tolerance test. In a subchronic study with ob/ob mice, YH-GKA showed significant decrease in blood glucose levels and no adverse effects on serum lipids or body weight. Overall, YH-GKA is a promising candidate for the therapy of type 2 diabetes mellitus. © 2012 The Pharmaceutical Society of Korea and Springer Science+Business Media Dordrecht.

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