Publications by authors named "Sang Dal Rhee"

47 Publications

T-Cell Death Associated Gene 51 Is a Novel Negative Regulator of PPARγ That Inhibits PPARγ-RXRα Heterodimer Formation in Adipogenesis

Mol Cells 2021 01;44(1):1-12

Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 34134, Korea.

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is the master transcriptional regulator in adipogenesis. PPARγ forms a heterodimer with another nuclear receptor, retinoid X receptor (RXR), to form an active transcriptional complex, and their transcriptional activity is tightly regulated by the association with either coactivators or corepressors. In this study, we identified T-cell death-associated gene 51 (TDAG51) as a novel corepressor of PPARγ-mediated transcriptional regulation. We showed that TDAG51 expression is abundantly maintained in the early stage of adipogenic differentiation. Forced expression of TDAG51 inhibited adipocyte differentiation in 3T3-L1 cells. We found that TDAG51 physically interacts with PPARγ in a ligand-independent manner. In deletion mutant analyses, large portions of the TDAG51 domains, including the pleckstrin homology-like, glutamine repeat and proline-glutamine repeat domains but not the proline-histidine repeat domain, are involved in the interaction with the region between residues 140 and 506, including the DNA binding domain, hinge, ligand binding domain and activation function-2 domain, in PPARγ. The heterodimer formation of PPARγ-RXRα was competitively inhibited in a ligand-independent manner by TDAG51 binding to PPARγ. Thus, our data suggest that TDAG51, which could determine adipogenic cell fate, acts as a novel negative regulator of PPARγ by blocking RXRα recruitment to the PPARγ-RXRα heterodimer complex in adipogenesis.
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http://dx.doi.org/10.14348/molcells.2020.0143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854182PMC
January 2021

Anticancer effect of XAV939 is observed by inhibiting lactose dehydrogenase A in a 3-dimensional culture of colorectal cancer cells.

Oncol Lett 2019 Nov 5;18(5):4858-4864. Epub 2019 Sep 5.

Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Republic of Korea.

XAV939, a tankyrase inhibitor, exerts an anticancer effect in 3-dimensional (3D) cultured SW480 cells, however this is not exhibited in 2-dimensional (2D) cultured SW480 cells. In the current study, XAV939 induced a 3.7-fold increase in cellular apoptosis in 3D culture but not in the 2D culture. However, no significant changes were indicated in cell cycle distribution in the 2D or 3D culture. Based on the observation that protein expression, which was associated with the glycolytic pathway, was increased in the 3D culture, the effect of XAV939 on the patterns of glycolytic protein expression was assessed. XAV939 was revealed to decrease lactose dehydrogenase A (LDHA) expression in 3D cultured SW480 cells, but only exerted a small effect in the 2D culture. The coadministration of XAV939 with the LDHA inhibitor FX11 decreased proliferation in 3D cultured SW480 cells compared with the single administration of FX11, while there was no additive effect in the 2D culture. The lactate assay also indicated that XAV939 decreased lactate secretion in the 3D cell culture but not in the 2D culture. These results suggest that XAV939 exerts an anticancer effect through inhibition of LDHA in the 3D culture.
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http://dx.doi.org/10.3892/ol.2019.10813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781734PMC
November 2019

Encapsulation and Enhanced Delivery of Topoisomerase I Inhibitors in Functionalized Carbon Nanotubes.

ACS Omega 2018 Jun 1;3(6):5938-5945. Epub 2018 Jun 1.

Advanced Materials Division and Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea.

The topoisomerase I inhibitors SN-38 and camptothecin (CPT) have shown potent anticancer activity, but water insolubility and metabolic instability limits their clinical application. Utilizing carbon nanotubes as a protective shell for water-insoluble SN-38 and CPT while maintaining compatibility with aqueous media via a carboxylic acid-functionalized surface can thus be a strategy to overcome this limitation. Through hydrophobic-hydrophobic interactions, SN-38 and CPT were successfully encapsulated in carboxylic acid functionalized single-walled carbon nanotubes and dispersed in water. The resulting cell proliferation inhibition and drug distribution profile inside the cells suggest that these drug-encapsulated carbon nanotubes can serve as a promising delivery strategy for water-insoluble anticancer drugs.
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http://dx.doi.org/10.1021/acsomega.8b00399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044808PMC
June 2018

Synthesis and biological evaluation of thiazole derivatives as GPR119 agonists.

Bioorg Med Chem Lett 2017 12 20;27(23):5213-5220. Epub 2017 Oct 20.

Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea. Electronic address:

A series of 4-(phenoxymethyl)thiazole derivatives was synthesized and evaluated for their GPR119 agonistic effect. Several 4-(phenoxymethyl)thiazoles with pyrrolidine-2,5-dione moieties showed potent GPR119 agonistic activities. Among them, compound 27 and 32d showed good in vitro activity with an EC value of 49 nM and 18 nM, respectively with improved human and rat liver microsomal stability compare with MBX-2982. Compound 27 &32d did not exhibit significant CYP inhibition, hERG binding, and cytotoxicity. Moreover, these compounds lowered the glucose excursion in mice in an oral glucose-tolerance test.
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http://dx.doi.org/10.1016/j.bmcl.2017.10.046DOI Listing
December 2017

Protective effects of carbenoxolone, an 11β-HSD1 inhibitor, against chemical induced dry eye syndrome.

Apoptosis 2017 Nov;22(11):1441-1453

Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea.

Dry eye syndrome (DES) is a disorder of the eye due to tear deficiency or excessive evaporation that causes damage to the eye and is associated with discomfort and dryness. 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) is an enzyme that converts inactive cortisone to active cortisol. Recently, 11β-HSD1 has been expressed in human and rodent eyes and has been recognized as a target of glaucoma. In this study, the therapeutic effects and underlying mechanisms of topical carbenoxolone, an 11β-HSD1 inhibitor, were investigated in benzalkonium chloride (BAC)-treated human conjunctival epithelial cells and a rat DES model. In the in vitro study, carbenoxolone dose-dependently inhibited cell death and 11β-HSD1 activity in BAC-treated human conjunctival epithelial cells. For the in vivo study, carbenoxolone or a solvent was administered to the BAC-induced DES model twice daily. BAC-treated rat eyes showed significant increases in ocular surface damage, a reduction of tears, decrease corneal thickness, corneal basement membrane destruction, apoptosis in the conjunctival epithelium, and expression of pro-inflammatory cytokines (TNF-α and IL-6) and 11β-HSD1. These effects of BAC were reversed by topical carbenoxolone treatment. These results demonstrate that carbenoxolone can prevent DES by inhibiting pro-inflammatory cytokine expression and cell death of the corneal and conjunctival epithelium via inhibition of both 11β-HSD1 activity and expression in the eyes of BAC-treated rats. It is suggested that topical 11β-HSD1 inhibitors may provide a new therapeutic window in the prevention and/or treatment of DES.
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http://dx.doi.org/10.1007/s10495-017-1419-6DOI Listing
November 2017

Cyp7a1 is continuously increased with disrupted Fxr-mediated feedback inhibition in hypercholesterolemic TALLYHO/Jng mice.

Biochim Biophys Acta Mol Cell Biol Lipids 2018 Jan 24;1863(1):20-25. Epub 2017 Aug 24.

Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, 141, Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, 99, Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea. Electronic address:

TALLYHO/Jng (TH) mice reveal hypercholesterolemia at an early age before their plasma glucose levels have increased. The increased plasma cholesterol should be related to bile acids (BAs) metabolism, because cholesterol is the precursor of BAs and BAs change cholesterol metabolism in a feedback manner. We analyzed the BAs pool size, BAs composition, and expression levels of several proteins that have key roles in BAs synthesis, excretion, and reabsorption and compared them to those of C57BL/6 (B6) mice to study BAs metabolism in TH mice. TH mice exhibited an increased total BAs pool size, increased BAs content in the cecum feces, and an increased ratio of muricholic acid (MCA)/cholic acid (CA). The mRNA and protein levels of cholesterol 7 alpha-hydroxylase (Cyp7a1) and the ATP-binding cassette sub-family G member 5 (Abcg5) were elevated in the liver but not in the apical sodium bile acid transporter (Asbt) and organic solute transporters (Osts) in the ileum. These results indicate that synthesis and the excretion of BAs from the liver to the gallbladder might be elevated, but the reabsorption rate of BAs in the ileum might be reduced. The declined expression of fibroblast growth factor 15 (Fgf15) and fibroblast growth factor receptor 4 (Fgfr4) was respectively identified in the ileum and the liver, indicating the disrupted feedback inhibition of Cyp7a1. Consequently, hypercholesterolemia in TH mice might increase the BAs amounts via the interrupted Fxr/Fgf15/Fgfr4-mediated feedback regulation of Cyp7a1.
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http://dx.doi.org/10.1016/j.bbalip.2017.08.007DOI Listing
January 2018

Design, synthesis, and biological evaluation of aryl N-methoxyamide derivatives as GPR119 agonists.

Bioorg Med Chem Lett 2017 08 13;27(16):3909-3914. Epub 2017 Jun 13.

Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea; Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea. Electronic address:

A series of N-methoxyamide derivatives was identified and evaluated as GPR119 agonists. Several N-methoxyamides with thienopyrimidine and pyridine scaffolds showed potent GPR119 agonistic activities. Among them, compound 9c displayed good in vitro activity and potency. Moreover, compound 9c lowered glucose excursion in mice in an oral glucose tolerance test and increased GLP-1 secretion in intestinal cells.
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http://dx.doi.org/10.1016/j.bmcl.2017.06.032DOI Listing
August 2017

Leptin induces CREB-dependent aromatase activation through COX-2 expression in breast cancer cells.

Food Chem Toxicol 2017 Aug 29;106(Pt A):232-241. Epub 2017 May 29.

Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea. Electronic address:

Leptin plays a key role in the control of adipocyte formation, as well as in the associated regulation of energy intake and expenditure. The goal of this study was to determine if leptin-induced aromatase enhances estrogen production and induces tumor cell growth stimulation. To this end, breast cancer cells were incubated with leptin in the absence or presence of inhibitor pretreatment, and changes in aromatase and cyclooxygenase-2 (COX-2) expression were evaluated at the mRNA and protein levels. Transient transfection assays were performed to examine the aromatase and COX-2 gene promoter activities and immunoblot analysis was used to examine protein expression. Leptin induced aromatase expression, estradiol production, and promoter activity in breast cancer cells. Protein levels of phospho-STAT3, PKA, Akt, ERK, and JNK were increased by leptin. Leptin also significantly increased cAMP levels, cAMP response element (CRE) activation, and CREB phosphorylation. In addition, leptin induced COX-2 expression, promoter activity, and increased the production of prostaglandin E. Finally, a COX-2 inhibitor and aromatase inhibitor suppressed leptin-induced cell proliferation in MCF-7 breast cancer cells. Together, our data show that leptin increased aromatase expression in breast cancer cells, which was correlated with COX-2 upregulation, mediated through CRE activation and cooperation among multiple signaling pathways.
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http://dx.doi.org/10.1016/j.fct.2017.05.058DOI Listing
August 2017

Fatty Liver and Insulin Resistance in the Liver-Specific Knockout Mice of Mitogen Inducible Gene-6.

J Diabetes Res 2016 7;2016:1632061. Epub 2016 Dec 7.

Research Center for Drug Discovery Technology, Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea; Department of Drug Development and Discovery, Graduate School of New Drug Development and Discovery, Chungnam National University, Daejeon, Republic of Korea.

Mitogen inducible gene-6 (Mig-6) is a feedback inhibitor of epidermal growth factor receptor (EGFR) signaling pathway. The liver-specific knockout mice of the Mig-6 gene (Mig-6 ) showed hepatomegaly and increased hypercholesterolemia. In this study, the biomarkers of insulin resistance and the effects of high-fat diets in the wild (Mig-6 ) and Mig-6 mice were analyzed. The fasting plasma concentrations of glucose, triglyceride, cholesterols, free fatty acids, and HOMA-IR were measured and the glucose tolerance and insulin resistance tests were performed in the 25-week-old Mig-6 and the Mig-6 mice. The protein levels of active insulin receptor, glucose 6-phosphatase, and phosphoenolpyruvate carboxykinase were analyzed in the liver and fat. The fasting plasma cholesterol and glucose concentration were higher in the Mig-6 mice than the Mig-6 mice with increased fat deposition in the liver. But the Mig-6 mice had the improved glucose intolerance and insulin resistance without increased amount of phosphoinsulin receptor after insulin infusion in the liver. The hepatic concentration of phosphoenolpyruvate carboxykinase was increased in fasting Mig-6 mice. The feeding of high-fat diet accelerated the plasma lipids profiles and HOMA-IR in the Mig-6 mice but had no differential effects in oral glucose tolerance test and insulin tolerance test in both genotypes. These results suggest that the activated EGFR signaling might increase the fasting plasma glucose concentration through inducing the hepatic steatosis and the improved whole-body insulin resistance in the KO mice be caused by decreased adipogenesis in fat tissues.
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http://dx.doi.org/10.1155/2016/1632061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5174183PMC
May 2017

Anti-inflammatory effect of a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor via the stimulation of heme oxygenase-1 in LPS-activated mice and J774.1 murine macrophages.

J Pharmacol Sci 2016 Aug 16;131(4):241-50. Epub 2016 Jul 16.

Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 305-764, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-333, Republic of Korea. Electronic address:

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inactive cortisone to the active cortisol. 11β-HSD1 may be involved in the resolution of inflammation. In the present study, we investigate the anti-inflammatory effects of 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone (KR-66344), a selective 11β-HSD1 inhibitor, in lipopolysaccharide (LPS)-activated C57BL/6J mice and macrophages. LPS increased 11β-HSD1 activity and expression in macrophages, which was inhibited by KR-66344. In addition, KR-66344 increased survival rate in LPS treated C57BL/6J mice. HO-1 mRNA expression level was increased by KR-66344, and this effect was reversed by the HO competitive inhibitor, ZnPP, in macrophages. Moreover, ZnPP reversed the suppression of ROS formation and cell death induced by KR-66344. ZnPP also suppressed animal survival rate in LPS plus KR-66344 treated C57BL/6J mice. In the spleen of LPS-treated mice, KR-66344 prevented cell death via suppression of inflammation, followed by inhibition of ROS, iNOS and COX-2 expression. Furthermore, LPS increased NFκB-p65 and MAPK phosphorylation, and these effects were abolished by pretreatment with KR-66344. Taken together, KR-66344 protects against LPS-induced animal death and spleen injury by inhibition of inflammation via induction of HO-1 and inhibition of 11β-HSD1 activity. Thus, we concluded that the selective 11β-HSD1 inhibitor may provide a novel strategy in the prevention/treatment of inflammatory disorders in patients.
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http://dx.doi.org/10.1016/j.jphs.2016.07.003DOI Listing
August 2016

Identification of a novel 11β-HSD1 inhibitor from a high-throughput screen of natural product extracts.

Pharmacol Res 2015 Dec 26;102:245-53. Epub 2015 Oct 26.

Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon, 305-333, Republic of Korea. Electronic address:

Selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) have considerable potential as a treatment for metabolic syndrome including type 2 diabetes mellitus and obesity. To identify 11β-HSD1 inhibitors, we conducted high-throughput screening (HTS) of active natural product extracts from the Korea Chemical Bank, including Tanshinone I, Tanshinone IIA, and flavanone derivatives, and 2- and 3-phenyl-4H-chromen-4-one. Then Tanshinone IIA and its derivatives were targeted for the development of a lead compound according to the HTS results. However, the mechanism for anti-adipogenic effect through 11β-HSD1 enzyme inhibition by Tanshinone IIA is not clear. Tanshinone IIA (2a) concentration-dependently inhibited 11β-HSD1 activity in human and mouse 11β-HSD1 overexpressed cells and 3T3-L1 adipocytes. Tanshinone IIA (2a) also inhibited 11β-HSD1 enzyme activities in murine liver and fats. Furthermore, Tanshinone IIA (2a)-suppressed adipocyte differentiation of cortisone-induced adipogenesis in 3T3-L1 cells was associated with the suppression of the cortisone-induced adipogenesis-specific markers mRNA and protein expression. In 3T3-L1 preadipocytes, Tanshinone IIA (2a)-inhibited cortisone induced reactive oxygen species formation in a concentration-dependent manner. Thus, these results support the therapeutic potential of Tanshinone IIA (2a) as a 11β-HSD1 inhibitor in metabolic syndrome patients.
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http://dx.doi.org/10.1016/j.phrs.2015.10.014DOI Listing
December 2015

Discovery and optimization of adamantane carboxylic acid derivatives as potent diacylglycerol acyltransferase 1 inhibitors for the potential treatment of obesity and diabetes.

Eur J Med Chem 2015 Aug 27;101:716-35. Epub 2015 Jun 27.

Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea; Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 305-333, Republic of Korea. Electronic address:

We have developed a series of adamantane carboxylic acid derivatives exhibiting potent diacylglycerol acyltransferase 1 (DGAT1) inhibitory activities. Optimization of the series led to the discovery of E-adamantane carboxylic acid compound 43c, which showed excellent in vitro activity with an IC50 value of 5 nM against human and mouse DGAT1, also good druggability as well as microsomal stability and safety profiles such as hERG, CYP and cytotoxicity. Compound 43c significantly reduced plasma triglyceride levels in vivo (in rodents and zebrafish) and also showed bodyweight gain reduction and glucose area under curve (AUC) lowering efficacy in diet-induced obesity (DIO) mice.
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http://dx.doi.org/10.1016/j.ejmech.2015.06.043DOI Listing
August 2015

Amelioration of hypercholesterolemia by an EGFR tyrosine kinase inhibitor in mice with liver-specific knockout of Mig-6.

PLoS One 2014 8;9(12):e114782. Epub 2014 Dec 8.

Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea.

Mitogen-inducible gene 6 (Mig-6) is a negative feedback inhibitor of epidermal growth factor receptor (EGFR) signaling. We previously found that Mig-6 plays a critical role in the regulation of cholesterol homeostasis and in bile acid synthesis. In this study, we investigated the effects of EGFR inhibition to identify a potential new treatment target for hypercholesterolemia. We used a mouse model with conditional ablation of the Mig-6 gene in the liver (Albcre/+Mig-6f/f; Mig-6d/d) to effectively investigate the role of Mig-6 in the regulation of liver function. Mig-6d/d mice were treated with either the EGFR inhibitor gefitinib or statin for 6 weeks after administration of a high-fat or standard diet. We then compared lipid profiles and other parameters among each group of mice. After a high-fat diet, Mig-6d/d mice showed elevated serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and glucose, characteristics resembling hypercholesterolemia in diabetic patients. We observed decreases in serum levels of lipids and glucose in high-fat-diet-fed Mig-6d/d mice after 6 weeks of treatment with gefitinib or statin. Furthermore gefitinib-treated mice showed significantly greater decreases in serum levels of total, HDL and LDL cholesterol compared with statin-treated mice. Taken together, these results suggest that EGFR inhibition is effective for the treatment of hypercholesterolemia in high-fat-diet-fed Mig-6d/d mice, and our findings provide new insights into the development of possible treatment targets for hypercholesterolemia via modulation of EGFR inhibition.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114782PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259477PMC
January 2016

Synthesis and biological evaluation of thienopyrimidine derivatives as GPR119 agonists.

Bioorg Med Chem Lett 2014 Sep 28;24(17):4281-5. Epub 2014 Jul 28.

Drug Discovery Division, Korea Research Institute of Chemical Technology, Republic of Korea; Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 305-333, Republic of Korea. Electronic address:

A series of thienopyrimidine derivatives was synthesized and evaluated for their GPR119 agonistic ability. Several thienopyrimidine derivatives containing R(1) and R(2) substituents displayed potent GPR119 agonistic activity. Among them, compound 5d, which is a prototype, showed good in vitro activity with an EC50 value of 3 nM and human and rat liver microsomal stability. Compound 5d exhibited no CYP inhibition and induction, Herg binding, or mutagenic potential. Compound 5d showed increase insulin secretion in beta TC-6 cell and lowered the glucose excursion in mice in an oral glucose-tolerance test.
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http://dx.doi.org/10.1016/j.bmcl.2014.07.020DOI Listing
September 2014

A novel 11β-HSD1 inhibitor improves diabesity and osteoblast differentiation.

J Mol Endocrinol 2014 Apr 6;52(2):191-202. Epub 2014 Mar 6.

Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea Division of Life and Pharmaceutical Sciences and Center for Cell Signaling and Drug Discovery Research, College of Pharmacy, Ewha Woman's University, Sedaemoon-gu, Seoul 120-750, Republic of Korea Laboratory of Translational Therapeutics, Korea Research Institute of Chemical Technology, Pharmacology Research Center, PO Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea Department of Toxicology, College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 305-764, Republic of Korea Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-333, Republic of Korea.

Selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) have considerable potential as treatment for osteoporosis as well as metabolic syndrome including type 2 diabetes mellitus. Here, we investigated the anti-diabetic, anti-adipogenic, and anti-osteoporotic activity of KR-67500, as a novel selective 11β-HSD1 inhibitor. Cellular 11β-HSD1 activity was tested based on a homogeneous time-resolved fluorescence method. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) levels were measured in diet-induced obese (DIO)-C57BL/6 mice administered KR-67500 (50  mg/kg per day, p.o.) for 28 days and, additionally, its anti-diabetic effect was evaluated by OGTT and ITT. The in vitro anti-adipogenic effect of KR-67500 was determined by Oil Red O Staining. The in vitro anti-osteoporotic activity of KR-67500 was evaluated using bone morphogenetic protein 2 (BMP2)-induced osteoblast differentiation and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation model systems. KR-67500 improved the in vivo glucose tolerance and insulin sensitivity in DIO-C57BL/6 mice. KR-67500 suppressed cortisone-induced differentiation of 3T3-L1 cells into adipocytes. KR-67500 enhanced BMP2-induced osteoblastogenesis in C2C12 cells and inhibited RANKL-induced osteoclastogenesis in mouse bone marrow-derived macrophages. KR-67500, a new selective 11β-HSD1 inhibitor, may provide a new therapeutic window in the prevention and/or treatment of type 2 diabetes, obesity, and/or osteoporosis.
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http://dx.doi.org/10.1530/JME-13-0177DOI Listing
April 2014

Anti-diabetic and anti-inflammatory effect of a novel selective 11β-HSD1 inhibitor in the diet-induced obese mice.

Eur J Pharmacol 2013 Dec 14;721(1-3):70-9. Epub 2013 Oct 14.

Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, P.O.Box 107, Yuseong-gu, Daejeon 305-600, Korea; Department of Toxicology, College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 305-764, Korea.

It has been reported that the selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) have considerable potential for treating type 2 diabetes mellitus, metabolic syndrome and inflammation. In the present study, we investigated the anti-diabetic and anti-inflammatory effects of N-(5-carbamoyladamantan-2-yl)-3-((2-fluorophenyl) sulfonyl)thiazolidine-2-carboxamide (KR-67105), a novel 11β-HSD1 inhibitor, in diabetic mice model and preadipocyte model. KR-67105 concentration dependently inhibited 11β-HSD1 activity in human and mouse 11β-HSD1 overexpressing cells and mouse 3T3-L1 adipocytes. Furthermore, KR-67105 concentration-dependently inhibited 11β-HSD1 activity in the ex vivo assay of C57BL/6 mice. In the study with diet-induced obese (DIO) mice, the administration of KR-67105 (100mg/kg/day, orally for 28 days) improved the glucose tolerance and insulin sensitivity as determined by the oral glucose tolerance test and the insulin tolerance test. Anti-diabetic effect by KR-67105 was associated with the suppression of diabetic related genes expression in liver and fat. Furthermore, KR-67105 suppressed 11β-HSD1 activity in liver and fat of diabetic mice, but showed no effect on adrenal grand weight/body weight ratio and plasma corticosterone concentration in diabetic mice. In 3T3-L1 preadipocytes, cortisone induced the mRNA of inflammatory cytokines and 11β-HSD1 and reactive oxygen species formation. This effect was abolished by co-incubation with KR-67105 in a concentration-dependent manner. Moreover, KR-67105 attenuated cortisone induced iNOS expression and phosphorylation of NF-κB p65, p38 MAPK, and ERK1/2 in preadipocytes. Taken together, it is concluded that a selective 11β-HSD1 inhibitor, KR-67105, may provide a new therapeutic window in the prevention and treatment of type 2 diabetes with chronic inflammation without toxicity.
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http://dx.doi.org/10.1016/j.ejphar.2013.09.052DOI Listing
December 2013

Synthesis and biological evaluation of aminobenzimidazole derivatives with a phenylcyclohexyl acetic acid group as anti-obesity and anti-diabetic agents.

Bioorg Med Chem Lett 2013 Aug 4;23(16):4713-8. Epub 2013 Jun 4.

Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.

A series of benzimidazole derivatives with a phenylcyclohexyl acetic acid group as DGAT-1 inhibitors was developed. Among the benzimidazole series, compound 5k showed submicromolar in vitro activity toward human and mouse DGAT-1, good selectivity toward DGAT-2, human liver metabolic stability, and pharmacokinetic (PK) and safety profiles such as hERG, CYP and acute toxicity. Additionally, 5k showed good in vivo efficacy in 4weeks study with DIO mouse model.
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http://dx.doi.org/10.1016/j.bmcl.2013.05.081DOI Listing
August 2013

Anti-diabetic and anti-adipogenic effects of a novel selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor in the diet-induced obese mice.

Eur J Pharmacol 2012 Sep 1;691(1-3):19-27. Epub 2012 Jul 1.

Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea.

Glucocorticoid excess (Cushing's syndrome) causes metabolic syndrome such as visceral obesity, insulin resistance, diabetes mellitus, dyslipidaemia and hypertension. The selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) have considerable potential for treating type 2 diabetes mellitus and metabolic syndrome. In the present study, we investigated the anti-diabetic and anti-adipogenic effects of 4-(2-(1,1-dioxido-6-(2,4,6-trichlorophenyl)-1,2,6-thiadiazinan-2-yl)acetamido)adamantane-1-carboxamide (KR-67183), a novel selective 11β-HSD1 inhibitor; we also investigated the underlying molecular mechanisms in the cortisone-induced 3T3-L1 adipogenesis model system and diet-induced obese (DIO) mice. KR-67183 concentration-dependently inhibited 11β-HSD1 activity in human and mouse 11β-HSD1 over-expressed cells and in the ex vivo assay of C57BL/6 mice. In the study with DIO mice, the administration of KR-67183 (20 and 50mg/kg/day, orally for 28 days) improved the glucose tolerance and insulin sensitivity with suppressed 11β-HSD1 activity in the liver and fat. However, KR-67183 showed no change in the adrenal gland weight/body weight ratio and plasma corticosterone concentration in DIO mice. Further, KR-67183 suppressed adipocyte differentiation on cortisone-induced adipogenesis in 3T3-L1 cells is associated with the suppression of the cortisone-induced mRNA levels of FABP4, PPARγ2 and GLUT4, and 11β-HSD1 activity. Taken together, it is suggested that a selective 11β-HSD1 inhibitor, KR-67183, may provide a new therapeutic window in the prevention and treatment without toxicity in type 2 diabetes with obesity.
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http://dx.doi.org/10.1016/j.ejphar.2012.06.024DOI Listing
September 2012

Carbenoxolone prevents the development of fatty liver in C57BL/6-Lep ob/ob mice via the inhibition of sterol regulatory element binding protein-1c activity and apoptosis.

Eur J Pharmacol 2012 Sep 26;691(1-3):9-18. Epub 2012 Jun 26.

Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong-gu, Daejeon, 305-600, Korea.

Carbenoxolone is the 3-hemisuccinate of glycyrrhetinic acid, the active principal of licorice (Glycyrrhiza glabra). It was reported that carbenoxolone improved glucose tolerance with increased insulin sensitivity in mice with high fat diet-induced obesity. In the present study, we elucidated the protective effect of carbenoxolone in fatty liver animal models of C57BL/6-Lep(ob/ob) mice through inhibition of hepatic lipogenesis and apoptosis. In addition, the potential mechanisms by which carbenoxolone could exert such protection were elucidated. Carbenoxolone was daily administrated by gavage for 28 days in C57BL/6 and C57BL/6-Lep(ob/ob) mice. Carbenoxolone prevented the plasma triglyceride and free fatty acid accumulation associated with the reduction of the expression of sterol regulatory element binding protein-1c, liver X receptor, fatty acid synthase and acethyl-CoA carboxylase in the livers of C57BL/6-Lep(ob/ob) mice. Carbenoxolone also prevented hepatic injury through anti-apoptotic action in the livers of C57BL/6-Lep(ob/ob) mice, accompanied by increased Bcl-2 expression and suppressed Bax and cytochrome c expression. As a mechanism, increased inflammatory cytokine expressions were inhibited by carbenoxolone in the fatty livers of C57BL/6-Lep(ob/ob) mice. Furthermore, carbenoxolone inhibited free fatty acid (oleate/palmitate) induced reactive oxygen species formation and reversed free fatty acid induced mitochondrial membrane depolarization in HepG2 cells. Carbenoxolone prevents the development of fatty liver by inhibiting sterol regulatory element binding protein-1c expression and activity with an anti-apoptotic mechanism via the inhibition of inflammatory cytokine and reactive oxygen species formation in the livers of C57BL/6-Lep(ob/ob) mice. It is suggested that carbenoxolone prevents the development and progression of fatty liver disease in patients with insulin resistance.
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http://dx.doi.org/10.1016/j.ejphar.2012.06.021DOI Listing
September 2012

Synthesis and biological evaluation of cyclic sulfamide derivatives as 11β-hydroxysteroid dehydrogenase 1 inhibitors.

ACS Med Chem Lett 2012 Feb 17;3(2):88-93. Epub 2012 Jan 17.

Bio-Organic Science Division, Korea Research Institute of Chemical Technology , Yuseong-Gu, Daejeon, 305-600, Korea.

A new series of cyclic sulfamide derivatives were synthesized and evaluated for their ability to inhibit 11β-HSD1. Among this series, 18e showed good in vitro activity toward human 11β-HSD1, selectivity against 11β-HSD2, microsomal stability, and pharmacokinetic and safety profiles (hERG, CYP, and acute toxicity). Additionally, 18e exhibited good in vivo efficacy in rat and monkey models.
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http://dx.doi.org/10.1021/ml200226xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025780PMC
February 2012

Pharmacokinetics and pharmacodynamics of KR-66223, a novel DPP-4 inhibitor.

Drug Metab Pharmacokinet 2012 13;27(2):216-22. Epub 2012 Jan 13.

Drug Discovery Platform Technology Team, Division of Bio-organic Science, Korea Research Institute of Chemical Technology, Daejeon.

KR-66223 is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes. We studied the pharmacokinetic and pharmacodynamic characteristics of KR-66223 in rats, monkeys, and dogs to predict PK/PD profiles in humans. KR-66223 exhibited a moderate volume of distribution (0.3-1.8 L/kg), moderate systemic clearance (1-1.76 L/h/kg), long half-life (>3 h), and low oral bioavailability (below 2.5% in all tested species). The EC(50)s for DPP-4 inhibition as calculated by the E(max) model was below 4.25 ng/mL across all species, confirming KR-66223 as a potent DPP-4 inhibitor. In vitro plasma protein binding suggested that it was available (69-89%), correlating with its volume of distribution in animals. Using allometric scaling and the E(max) model, human systemic clearance, volume of the central compartment, volume of the peripheral compartment, and EC₅₀ for DPP-4 inhibition were predicted to be 0.31 L/h/kg, 0.1 L/kg, 2.4 L/kg, and 3 ng/mL, respectively. These results can serve as a valuable foundation for future clinical trials.
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http://dx.doi.org/10.2133/dmpk.dmpk-11-rg-095DOI Listing
January 2013

Lysophosphatidylcholine as an effector of fatty acid-induced insulin resistance.

J Lipid Res 2011 Jun 28;52(6):1234-46. Epub 2011 Mar 28.

Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.

The mechanism of FFA-induced insulin resistance is not fully understood. We have searched for effector molecules(s) in FFA-induced insulin resistance. Palmitic acid (PA) but not oleic acid (OA) induced insulin resistance in L6 myotubes through C-Jun N-terminal kinase (JNK) and insulin receptor substrate 1 (IRS-1) Ser307 phosphorylation. Inhibitors of ceramide synthesis did not block insulin resistance by PA. However, inhibition of the conversion of PA to lysophosphatidylcholine (LPC) by calcium-independent phospholipase A₂ (iPLA₂) inhibitors, such as bromoenol lactone (BEL) or palmitoyl trifluoromethyl ketone (PACOCF₃), prevented insulin resistance by PA. iPLA₂ inhibitors or iPLA₂ small interfering RNA (siRNA) attenuated JNK or IRS-1 Ser307 phosphorylation by PA. PA treatment increased LPC content, which was reversed by iPLA₂ inhibitors or iPLA₂ siRNA. The intracellular DAG level was increased by iPLA₂ inhibitors, despite ameliorated insulin resistance. Pertussis toxin (PTX), which inhibits LPC action through the G-protein coupled receptor (GPCR)/Gα(i), reversed insulin resistance by PA. BEL administration ameliorated insulin resistance and diabetes in db/db mice. JNK and IRS-1Ser307 phosphorylation in the liver and muscle of db/db mice was attenuated by BEL. LPC content was increased in the liver and muscle of db/db mice, which was suppressed by BEL. These findings implicate LPC as an important lipid intermediate that links saturated fatty acids to insulin resistance.
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http://dx.doi.org/10.1194/jlr.M014787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3090244PMC
June 2011

Inhibitory effect of leptin on rosiglitazone-induced differentiation of primary adipocytes prepared from TallyHO/Jng mice.

Biochem Biophys Res Commun 2011 Mar 23;406(4):584-9. Epub 2011 Feb 23.

Medicinal Science Division, Korea Research Institute of Chemical Technology, 100 Jang-dong, Yuseong, 305-600 Daejon, Republic of Korea.

The effects of leptin on rosiglitazone-induced adipocyte differentiation were investigated in the primary adipocytes prepared from subcutaneous fat of TallyHO/Jng (TallyHO) mouse, a recently developed model animal for type 2 diabetes mellitus (T2DM). The treatment of leptin inhibited the rosiglitazone-induced adipocyte differentiation with a decreased expression of peroxisome proliferator-activated receptor γ (PPARγ) a key adipogenic transcription factor, both in mRNA and protein levels. Leptin (10 nM) was sufficient to inhibit the adipocyte differentiation, which seemed to come from increased expression of leptin receptor genes in the fat of TallyHO mice. The inhibition of adipogenesis by leptin was restored by the treatment of inhibitors for extracellular-signal-regulated kinase (ERK) (PD98059) and signal transducer and activator of transcription-1 (STAT1) (fludarabine). Furthermore, in vivo intraperitoneal administration of PD98059 and fludarabine increased the PPARγ expression in the subcutaneous fat of TallyHO mice. These data suggest that leptin could inhibit the PPARγ expression and adipocyte differentiation in its physiological concentration in TallyHO mice.
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http://dx.doi.org/10.1016/j.bbrc.2011.02.095DOI Listing
March 2011

Anti-diabetic and anti-adipogenic effects of a novel selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone (KR-66344).

Biochem Pharmacol 2011 Apr 18;81(8):1028-35. Epub 2011 Feb 18.

Bio-Organic Science Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea.

The selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) have considerable potential for treating type 2 diabetes mellitus and metabolic syndrome. In the present study, we investigated the anti-diabetic and anti-adipogenic effects of 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone (KR-66344), as a 11β-HSD1 inhibitor; we also investigated the underlying molecular mechanisms in the cortisone-induced 3T3-L1 adipogenesis model system and C57BL/6-Lep(ob/ob) mice. KR-66344 concentration-dependently inhibited 11β-HSD1 activity in human liver microsome, mouse C2C12 myotube and human SW982 cells. In the C57BL/6-Lep(ob/ob) mice study, the administration of KR-66344 (200mg/kg/d, orally for 5 days) improved the glucose intolerance as determined by the oral glucose tolerance test, in which the area under the curve (AUC) of the plasma glucose concentration was significantly reduced by 27% compared with the vehicle treated group. Further, KR-66344 suppressed adipocyte differentiation on cortisone-induced adipogenesis in 3T3-L1 cells is associated with the suppression of the cortisone-induced mRNA levels of FABP4, G3PD, PPARγ2 and Glut4, and 11β-HSD1 expression and activity. Our results additionally demonstrate evidence showing that KR-66344 improved glycemic control and inhibited adipogenesis via 11β-HSD1 enzyme activity. Taken together, these results may provide evidence of the therapeutic potential of KR-66344, as a 11β-HSD1 inhibitor, in obesity and type 2 diabetes patients with metabolic syndrome.
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http://dx.doi.org/10.1016/j.bcp.2011.01.020DOI Listing
April 2011

Discovery of β-aminoacyl containing thiazolidine derivatives as potent and selective dipeptidyl peptidase IV inhibitors.

Bioorg Med Chem Lett 2011 Mar 14;21(5):1366-70. Epub 2011 Jan 14.

Drug Discovery Division, Korea Research Institute of Chemical Technology, Yuseong-Gu, Daejeon, Republic of Korea.

A series of β-aminoacyl containing thiazolidine derivatives was synthesized and evaluated for their ability to inhibit DPP-IV. Several thiazolidine derivatives with an acid moiety were found to be potent DPP-IV inhibitors. Among them, compound 2da is the most active in this series with an IC(50) value of 1 nM, and it showed excellent selectivity over DPP-IV related enzymes including DPP-2, DPP-8, and DPP-9. Compound 2da is chemically and metabolically stable, and showed no CYP inhibition, hERG binding or cytotoxicity. Compound 2db, an ester prodrug of 2da, showed good in vivo DPP-IV inhibition after oral administration in rat and dog models.
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http://dx.doi.org/10.1016/j.bmcl.2011.01.041DOI Listing
March 2011

Identification of cyclicsulfonamide derivatives with an acetamide group as 11β-hydroxysteroid dehydrogenase 1 inhibitors.

Chem Pharm Bull (Tokyo) 2011 ;59(1):46-52

Department of Chemistry, Korea University, Seoul, Korea.

In the continuation of our 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor research, cyclic sulfonamide derivatives with an acetamide group at the 2-position were synthesized and evaluated for their abilities to inhibit 11β-HSD1. Among this series, Compound 34 showed good in vitro activity toward human 11β-HSD1, selectivity against 11β-HSD2, microsomal stability, good pharmacokinetic and safety profiles human ether-a-go-go related gene (hERG and cytochrome P450 (CYP)). Also, a docking study explained the activity difference between human and mouse 11β-HSD1.
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http://dx.doi.org/10.1248/cpb.59.46DOI Listing
April 2011

Synthesis and 11β hydroxysteroid dehydrogenase 1 inhibition of thiazolidine derivatives with an adamantyl group.

Bioorg Med Chem Lett 2011 Jan 2;21(1):435-9. Epub 2010 Nov 2.

Department of Chemistry, Korea University, Seoul 136-701, Republic of Korea.

A new series of thiazolidine derivatives with an adamantyl group was synthesized and evaluated for their ability to inhibit 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). Our initial compound 5a showed a weak inhibitory activity. Significant improvements in potency were achieved by substituent modification. The potent compound 8g (E) showed good in vitro inhibitory activity toward human 11β-HSD1, selectivity toward 11β-HSD2, metabolic stability, pharmacokinetic, and safety profile. Furthermore, this compound significantly inhibited 11β-HSD1 activity in rat and monkey models, and showed improved glycemic control in KKAy mice.
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http://dx.doi.org/10.1016/j.bmcl.2010.10.123DOI Listing
January 2011

Selective inhibition of activated stellate cells and protection from carbon tetrachloride-induced liver injury in rats by a new PPARgamma agonist KR62776.

Arch Pharm Res 2010 Mar 30;33(3):433-42. Epub 2010 Mar 30.

Drug Discovery Platform Technology Team, Medicinal Science Division, Korea Research Institute of Chemical Technology, Daejon, 305-600, Korea.

Activated hepatic stellate cells (HSC) are the primary source of extracellular matrix proteins found in liver fibrosis/cirrhosis patients. Therefore, the prevention of HSC activation is an important strategy for treating severe liver injury. This study examined the effects of KR62776, a new peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, on the rate of cell proliferation and expression of alpha-smooth muscle actin (alpha-SMA) in rat hepatic stellate HSC-T6 cells. In addition, its effects on the liver damage induced by carbon tetrachloride were investigated. KR62776 caused the apoptosis of activated HSC-T6 cells with the concomitant decrease in the alpha-smooth muscle actin levels in a time- and concentration-dependent manner. However, KR62776 did not cause the apoptosis of human HepG2 and rat McARH7777 hepatoma cells, suggesting that KR62776 has a specific effect on stellate cells. KR62776 increased the levels of Gadd45, p27, p21 and PPARgamma proteins but decreased the cell cyclerelated proteins, such as cdk2, cyclin B and cyclin D1. These changes were reversed by BADGE, a specific PPARgamma antagonist, indicating that the effects of KR62776 are, at least in part, PPARgamma-dependent. In addition, KR62776 administration showed some protection against carbon tetrachloride-induced hepatocellular damage in rats. Overall, these results suggest that KR62776 may have potential in the chemoprevention of liver fibrosis/cirrhosis.
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http://dx.doi.org/10.1007/s12272-010-0313-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835440PMC
March 2010

Discovery of cyclicsulfonamide derivatives as 11 beta-hydroxysteroid dehydrogenase 1 inhibitors.

Bioorg Med Chem Lett 2010 Feb 11;20(3):1065-9. Epub 2009 Dec 11.

Department of Chemistry, Korea University, Seoul 121-742, Republic of Korea.

A new series of cyclic sulfonamide derivatives was synthesized and evaluated for their ability to inhibit 11beta-HSD1. Cyclic sulfonamides with phenylacetyl substituents at the 2-position showed nanomolar inhibitory activities. Among them, compound 4e exhibited a good in vitro inhibitory activity and selectivity toward human 11beta-HSD2.
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http://dx.doi.org/10.1016/j.bmcl.2009.12.035DOI Listing
February 2010

Small intestine submucosa sponge for in vivo support of tissue-engineered bone formation in the presence of rat bone marrow stem cells.

Biomaterials 2010 Feb 24;31(6):1104-13. Epub 2009 Oct 24.

Nano Bio Fusion Research Center, Korea Research Institute of Chemical Technology, P. O. Box 107, Yuseung, Daejeon 305-600, Republic of Korea.

The aim of the current study was to visualize new bone formed in vivo on a small intestine submucosa (SIS) sponge used as a tissue-engineered scaffold for the repair of damaged bone. The SIS sponge provided a three-dimensional pore structure, and supported good attachment and viability of rat bone marrow stem cells (rBMSCs). To examine bone regeneration, we prepared full-thickness bilateral bone defects in the rat crania, and then treated the defects with an implanted SIS sponge or PGA mesh without or with rBMSCs, or left the defects untreated. Bone defects were evaluated by micro-CT and histologically after 2 and 4 weeks. Micro-CT demonstrated a trend toward a decrease in bone void in both the SIS sponge and SIS sponge/rBMSCs groups compared to the control and PGA mesh groups. At 4 weeks, bone formation in defects containing SIS sponge/rBMSCs was significantly greater than in all other groups. A histological analysis after 2 and 4 weeks of implantation showed localized collagen and osteocalcin deposition on SIS sponges and SIS sponges with rBMSCs. These in vivo results indicate that the SIS sponge, implanted at bone-removal defects, facilitated bone regeneration.
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http://dx.doi.org/10.1016/j.biomaterials.2009.10.020DOI Listing
February 2010