Eunkyung Kim - Academia.edu (original) (raw)
Papers by Eunkyung Kim
European Journal of Pharmacology, 2011
Peroxisome proliferator-activated receptor (PPAR) γ is known to be a key regulator of insulin res... more Peroxisome proliferator-activated receptor (PPAR) γ is known to be a key regulator of insulin resistance. PAM-1616 is a novel, non-thiazolidinedione small molecule compound synthesized in Dong-A Research Center. In this study, we characterized the pharmacological and safety profiles of PAM-1616 as a selective PPARγ modulator. PAM-1616 selectively binds to human PPARγ (IC 50 , 24.1 ± 5.6 nM) and is a partial agonist for human PPARγ with an EC 50 of 83.6 ± 43.7 nM and a maximal response of 24.9 ± 7.1% relative to the full agonist, rosiglitazone. PAM-1616 was selective for human PPARγ than for human PPARα (EC 50 , 2658± 828 nM) without activating human PPARδ, which makes it a selective modulator of PPARγ. Treatment of high fat diet-induced obese C57BL/6J mice with PAM-1616 for 21 days improved HOMA-IR. Furthermore, PAM-1616 significantly improved hyperglycemia in db/db mice with little side effect when orally administered at a dose of 1 mg/kg/day for 28 days. Intriguingly, PAM-1616 was seen to increase the gene expression of inducible glucose transporter (GLUT4), while it partially induced that of a fatty acid carrier, aP2 in 3T3-L1 adipocytes, and it also showed partial recruitment of an adipogenic cofactor, TRAP220 as compared to rosiglitazone. PAM-1616 did not cause a significant increase in plasma volume of ICR mice when orally administered at a dose of 10 mg/kg/day for 9 days. PAM-1616 increased the expression of fluid retentioninducing genes such as serum/glucocorticoid-regulated kinase (SGK)-1 to a lesser extent as compared to rosiglitazone in human renal epithelial cells. These results suggest that PAM-1616 acts as a selective modulator of PPARγ with excellent antihyperglycemic property. The differential modulation of target gene by PAM-1616 might contribute to the improved side effect profiles.
European Journal of Pharmacology, 2008
Peroxisome proliferator-activated receptor (PPAR) α and γ are key regulators of lipid homeostasis... more Peroxisome proliferator-activated receptor (PPAR) α and γ are key regulators of lipid homeostasis and insulin resistance. In this study, we characterize the pharmacological profiles of PAR-5359, a dual agonist of PPARα and γ with well-balanced activities. In transient transactivation assay, PAR-5359 (3-(4-{2[4-(4chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethoxy}-phenyl)-(2S)-ethoxy-propionic acid) significantly activated human and mouse PPARα and γ without activating PPARδ. In functional assays using human mesenchymal stem cells and human hepatoma HepG2 cells, PAR-5359 significantly induced adipocyte differentiation and human ApoA1 secretion, which coincided with its transactivation potencies against the corresponding human receptor subtypes. Interestingly, PAR-5359 showed equivalent potencies against the mouse receptor subtypes (α and γ; 2.84 μM and 3.02 μM, respectively), which suggests the possibility that PAR-5359 could simultaneously activates each subtype of receptors subtype in under physiological conditions. In an insulinresistant ob/ob mouse model, PAR-5359 significantly reduced plasma insulin levels, improved insulin sensitivity (HOMA-IR), and completely normalized plasma glucose levels. In a severe diabetic db/db mouse model, PAR-5359 dose-dependently reduced the plasma levels of glucose (ED 30 = 0.07 mg/kg). Furthermore, it lowered plasma levels of non HDL-(ED 30 = 0.13 mg/kg) and total cholesterol (ED 30 = 0.03 mg/kg) in high cholesterol diet-fed rats for 4 days treatment. These results suggest that PAR-5359 has the balanced activities for PPARα and PPARγ in vivo as well as in vitro. And its balanced activities may render PAR-5359 as a pharmacological tool in elucidating the complex roles of PPARα/γ dual agonists.
![Research paper thumbnail of Total Synthesis of Pancratistatin Relying on the [3,3]-Sigmatropic Rearrangement](https://attachments.academia-assets.com/102726049/thumbnails/1.jpg)
](The Journal of Organic Chemistry, 2004
A new total synthesis of the antitumor alkaloid, pancratistatin (1), has been accomplished from r... more A new total synthesis of the antitumor alkaloid, pancratistatin (1), has been accomplished from readily available starting materials. Claisen rearrangement of the racemic dihydropyranethylene 17 was employed to construct the A and C rings with the appropriate stereochemistry. In addition, the Ireland-Claisen rearrangement of the enantiomerically pure 9 followed by ring-closing metathesis provided the important intermediate 24, thus implying that our approach could yield the enantioselective synthesis of (+)-pancratistatin. With the appropriately functionalized cyclohexene 24, stereo-and regiocontrolled functional group interchanges, such as iodolactonization, dihydroxylations, and a cyclic sulfate elimination reaction, facilitated the production of the target natural product.
European Journal of Pharmacology, 2011
Peroxisome proliferator-activated receptor (PPAR) γ is known to be a key regulator of insulin res... more Peroxisome proliferator-activated receptor (PPAR) γ is known to be a key regulator of insulin resistance. PAM-1616 is a novel, non-thiazolidinedione small molecule compound synthesized in Dong-A Research Center. In this study, we characterized the pharmacological and safety profiles of PAM-1616 as a selective PPARγ modulator. PAM-1616 selectively binds to human PPARγ (IC 50 , 24.1 ± 5.6 nM) and is a partial agonist for human PPARγ with an EC 50 of 83.6 ± 43.7 nM and a maximal response of 24.9 ± 7.1% relative to the full agonist, rosiglitazone. PAM-1616 was selective for human PPARγ than for human PPARα (EC 50 , 2658± 828 nM) without activating human PPARδ, which makes it a selective modulator of PPARγ. Treatment of high fat diet-induced obese C57BL/6J mice with PAM-1616 for 21 days improved HOMA-IR. Furthermore, PAM-1616 significantly improved hyperglycemia in db/db mice with little side effect when orally administered at a dose of 1 mg/kg/day for 28 days. Intriguingly, PAM-1616 was seen to increase the gene expression of inducible glucose transporter (GLUT4), while it partially induced that of a fatty acid carrier, aP2 in 3T3-L1 adipocytes, and it also showed partial recruitment of an adipogenic cofactor, TRAP220 as compared to rosiglitazone. PAM-1616 did not cause a significant increase in plasma volume of ICR mice when orally administered at a dose of 10 mg/kg/day for 9 days. PAM-1616 increased the expression of fluid retentioninducing genes such as serum/glucocorticoid-regulated kinase (SGK)-1 to a lesser extent as compared to rosiglitazone in human renal epithelial cells. These results suggest that PAM-1616 acts as a selective modulator of PPARγ with excellent antihyperglycemic property. The differential modulation of target gene by PAM-1616 might contribute to the improved side effect profiles.
European Journal of Pharmacology, 2008
Peroxisome proliferator-activated receptor (PPAR) α and γ are key regulators of lipid homeostasis... more Peroxisome proliferator-activated receptor (PPAR) α and γ are key regulators of lipid homeostasis and insulin resistance. In this study, we characterize the pharmacological profiles of PAR-5359, a dual agonist of PPARα and γ with well-balanced activities. In transient transactivation assay, PAR-5359 (3-(4-{2[4-(4chlorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethoxy}-phenyl)-(2S)-ethoxy-propionic acid) significantly activated human and mouse PPARα and γ without activating PPARδ. In functional assays using human mesenchymal stem cells and human hepatoma HepG2 cells, PAR-5359 significantly induced adipocyte differentiation and human ApoA1 secretion, which coincided with its transactivation potencies against the corresponding human receptor subtypes. Interestingly, PAR-5359 showed equivalent potencies against the mouse receptor subtypes (α and γ; 2.84 μM and 3.02 μM, respectively), which suggests the possibility that PAR-5359 could simultaneously activates each subtype of receptors subtype in under physiological conditions. In an insulinresistant ob/ob mouse model, PAR-5359 significantly reduced plasma insulin levels, improved insulin sensitivity (HOMA-IR), and completely normalized plasma glucose levels. In a severe diabetic db/db mouse model, PAR-5359 dose-dependently reduced the plasma levels of glucose (ED 30 = 0.07 mg/kg). Furthermore, it lowered plasma levels of non HDL-(ED 30 = 0.13 mg/kg) and total cholesterol (ED 30 = 0.03 mg/kg) in high cholesterol diet-fed rats for 4 days treatment. These results suggest that PAR-5359 has the balanced activities for PPARα and PPARγ in vivo as well as in vitro. And its balanced activities may render PAR-5359 as a pharmacological tool in elucidating the complex roles of PPARα/γ dual agonists.
The Journal of Organic Chemistry, 2004
A new total synthesis of the antitumor alkaloid, pancratistatin (1), has been accomplished from r... more A new total synthesis of the antitumor alkaloid, pancratistatin (1), has been accomplished from readily available starting materials. Claisen rearrangement of the racemic dihydropyranethylene 17 was employed to construct the A and C rings with the appropriate stereochemistry. In addition, the Ireland-Claisen rearrangement of the enantiomerically pure 9 followed by ring-closing metathesis provided the important intermediate 24, thus implying that our approach could yield the enantioselective synthesis of (+)-pancratistatin. With the appropriately functionalized cyclohexene 24, stereo-and regiocontrolled functional group interchanges, such as iodolactonization, dihydroxylations, and a cyclic sulfate elimination reaction, facilitated the production of the target natural product.