FK614
目录号 : GC62974
FK614 是一种具有口服活性，有效的，选择性的 PPARγ 调制剂 (SPPARM)。FK614 对脂肪细胞分化各阶段 PPARγ 的激活有不同的影响。FK614 是一种非噻唑烷二酮类胰岛素增敏剂。FK614 可用于高血糖、高甘油三酯、葡萄糖耐受不良和 2 型糖尿病的研究。
Cas No.:193012-35-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
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- Datasheet
FK614 is an orally active, potent, selective PPARγ modulator (SPPARM). FK614 has different effects on the activation of PPARγ at each stage of adipocyte differentiation. FK614 is a nonthiazolidinedione insulin sensitizer. FK614 can be used for the research of hyperglycemia, hypertriglyceridemia, glucose intolerance and type 2 diabetes[1][2][3].
FK614 (0.1~10000 nM; 24 hours; CV-1 cells) activates PPARγ-dependent transcription in a concentration-dependent manner. FK614 (0~0.1 μM; 5 days; 3T3-L1 adipocytes) makes triglyceride content increased in a concentration-dependent manner. FK614 has different effects on the activation of PPARγ at each stage of adipocyte differentiation. FK614 is an insulin sensitizer potentially for treatment of postherpetic neuralgia[1][2].
FK614 (0.32~3.2 mg/kg; p.o.; 14 days) dose-dependently reduces plasma glucose level[3].FK614 (0.1~10 mg/kg; p.o.; 14 days) improves the impaired glucose tolerance[3].
[1]. Fujimura T, et al. A selective peroxisome proliferator-activated receptor gamma modulator with distinct fat cell regulation properties. J Pharmacol Exp Ther. 2006;318(2):863-871.
[2]. Fujimura T, et al. FK614, a novel peroxisome proliferator-activated receptor gamma modulator, induces differential transactivation through a unique ligand-specific interaction with transcriptional coactivators. J Pharmacol Sci. 2005;99(4):342-352.
| Cas No. | 193012-35-0 | SDF | |
| 分子式 | C21H23Cl2N3O3S | 分子量 | 468.4 |
| 溶解度 | DMSO : 100 mg/mL (213.49 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1349 mL | 10.6746 mL | 21.3493 mL |
| 5 mM | 0.427 mL | 2.1349 mL | 4.2699 mL |
| 10 mM | 0.2135 mL | 1.0675 mL | 2.1349 mL |
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FK614, a novel peroxisome proliferator-activated receptor gamma modulator, induces differential transactivation through a unique ligand-specific interaction with transcriptional coactivators
J Pharmacol Sci 2005 Dec;99(4):342-52.PMID:16314690DOI:10.1254/jphs.fp0050578.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcriptional factor implicated in regulating adipogenesis, glucose homeostasis, and in mediating the action of the insulin sensitizing anti-diabetic thiazolidinedione (TZD) compounds. [3-(2,4-Dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3-H-benzimidazole-5-carboxamide] (FK614) is a structurally novel PPARgamma agonist that demonstrates potent anti-diabetic activity in vivo. Herein, we describe that FK614 is a selective PPARgamma ligand with specific transactivation properties that are dependent upon the context of coactivators. FK614 dissociates the corepressors NCoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors) from PPARgamma as effectively as rosiglitazone and pioglitazone, but can also differentially induce a ligand specific interaction of PPARgamma with coactivators. The amount of CBP (CREB-binding protein) and SRC-1 (steroid receptor coactivator-1) recruited by FK614 was less than that induced by rosiglitazone and pioglitazone, but FK614 caused similar PGC-1alpha (PPARgamma coactivator-1alpha) recruitment as these compounds. As a consequence of these ligand-specific differences in the strength of ligand-type specific interactions of PPARgamma and coactivators, FK614 functions as a partial or full agonist for transcriptional activation depending upon the amount of specific coactivators in cells following overexpression. In conclusion, FK614 is a novel, non-TZD type, and selective PPARgamma modulator whose pharmacological properties are distinct from rosiglitazone and pioglitazone.
Ameliorating effect of FK614, a novel nonthiazolidinedione peroxisome proliferator-activated receptor gamma agonist, on insulin resistance in Zucker fatty rat
Eur J Pharmacol 2005 Sep 5;519(1-2):182-90.PMID:16039648DOI:10.1016/j.ejphar.2005.05.042.
Effect of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide (FK614), a novel nonthiazolidinedione peroxisome proliferator-activated receptor (PPAR) gamma agonist, on glucose tolerance and insulin resistance in peripheral tissues and in liver using Zucker fatty rats (genetically obese and insulin-resistant) was evaluated and compared to other insulin sensitizers. FK614 (0.32, 1 and 3.2 mg/kg), two thiazolidinedione PPAR gamma agonists, rosiglitazone (0.1, 0.32, 1 and 3.2 mg/kg) and pioglitazone (1, 3.2 and 10 mg/kg), and a biguanide, metformin (320 and 1000 mg/kg), were orally administered to Zucker fatty rats once a day for 14 days. Zucker fatty rats treated with FK614 and rosiglitazone were subjected to evaluation by oral glucose tolerance test. Ameliorating effect of each compound on peripheral and hepatic insulin resistance was evaluated using a euglycemic-hyperinsulineamic clamp procedure. FK614 and rosiglitazone dose-dependently improved impaired glucose tolerance in Zucker fatty rats. In addition, FK614 dose-dependently ameliorated peripheral and hepatic insulin resistance in Zucker fatty rats, with the degree of its effect in peripheral tissues almost equivalent to that in liver when compared at each dose tested. Similar data indicating ameliorating effects on insulin resistance was obtained for rosiglitazone and pioglitazone. Metformin showed less potent effects than other insulin sensitizers and its effect in liver tended to be greater than that in peripheral tissues. These findings suggest clinical potential for FK614 as a treatment of type 2 diabetes, acting by ameliorating insulin resistance both in peripheral tissues and liver.
Pharmacological characteristics of a novel nonthiazolidinedione insulin sensitizer, FK614
Eur J Pharmacol 2004 Jun 28;494(2-3):273-81.PMID:15212984DOI:10.1016/j.ejphar.2004.04.038.
We evaluated antidiabetic effects of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3 H-benzimidazole-5-carboxamide (FK614), a benzimidazole derivative without a thiazolidinedione structure, which was obtained using C57BL/KsJ-db/db mice (db/db mice). In db/db mice, the potency of FK614 for hypoglycemic effect was comparable to that of rosiglitazone and approximately 15-fold greater than that of pioglitazone. FK614 also showed a potent attenuating effect on hypertriglyceridemia in db/db mice, as well as rosiglitazone and pioglitazone. In C57BL/6J-ob/ob mice (ob/ob mice), ED(50) values of FK614 and pioglitazone for hypoinsulinemic effect were 1.3 and 11.8 mg/kg, respectively. FK614 also improved the impaired glucose tolerance in ob/ob mice. In normal rats, FK614 did not influence plasma glucose and insulin levels but significantly decreased both plasma triglyceride and nonesterified fatty acid levels. FK614 was found to activate peroxisome proliferator-activated receptor (PPAR)gamma-mediated transcriptional activity in the reporter gene assay as well as thiazolidinedione derivatives, although its maximum effect was less than that of thiazolidinedione derivatives. In rat toxicity studies, hemodilution effects for FK614 were less than that for rosiglitazone. Overall, these studies suggest that FK614 improves insulin resistance in such animal models through activation of PPARgamma-mediated transcriptional activity and that it would be a new therapeutic candidate with potential for the treatment of type 2 diabetic patients.
Unique properties of coactivator recruitment caused by differential binding of FK614, an anti-diabetic agent, to peroxisome proliferator-activated receptor gamma
Biol Pharm Bull 2006 Mar;29(3):423-9.PMID:16508139DOI:10.1248/bpb.29.423.
FK614 is a structurally novel class of peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, with the mechanism of its insulin-sensitizing action most likely due to activation of PPARgamma. In this study, properties of FK614 for PPARgamma binding, ability to induce conformational change, and coactivator recruitment were investigated. FK614, rosiglitazone, and pioglitazone competed specific binding of [3H]rosiglitazone to PPARgamma with Ki values of 11 nM, 47 nM, and 1.3 microM, respectively. Limited trypsin digestion of PPARgamma with FK614 or rosiglitazone produced distinct patterns of digested polypeptides, suggesting that FK614 directly binds to PPARgamma but induces specific alterations in receptor conformation. FK614 induced interaction of PPARgamma with nuclear receptor coactivator CBP but of lower magnitude than rosiglitazone and pioglitazone. The estimated Kd values of FK614-, rosiglitazone-, and pioglitazone-PPARgamma complex to CBP peptide were 1.8, 0.64, and 0.72 microM, respectively, indicating FK614-PPARgamma complex exhibits a lower affinity for CBP peptide compared to other agonist-PPARgamma complexes. When tested the effect of FK614 on CBP recruitment induced by 9(S)-hydroxyoctadecadienoic acid, an endogenous ligand, FK614 negatively modulated PPARgamma activation. The unique properties of FK614 may underlie the molecular basis of ligand-dependent transcriptional modulation mediated by PPARgamma.
Mechanism by which a novel non-thiazolidinedione peroxisome proliferator-activated receptor gamma agonist, FK614, ameliorates insulin resistance in Zucker fatty rats
Diabetes Obes Metab 2007 May;9(3):369-78.PMID:17391165DOI:10.1111/j.1463-1326.2006.00619.x.
Aim: The aim of this study was to examine the mechanism by which a novel non-thiazolidinedione (TZD) peroxisome proliferator-activated receptor (PPAR) gamma agonist, FK614, ameliorates insulin resistance in Zucker fatty rats. Methods: FK614 (1, 3.2 or 10 mg/kg) and a TZD PPARgamma agonist, pioglitazone (1, 3.2 or 10 mg/kg), were orally administered to Zucker fatty rats (genetically obese and insulin resistant) once a day for 14 days, and an oral glucose tolerance test was performed. The expression levels of various genes in the white adipose tissue (WAT) of Zucker fatty rats treated with FK614 (3.2 mg/kg), pioglitazone (10 mg/kg) and another TZD PPARgamma agonist, rosiglitazone (3.2 mg/kg), were determined using a real-time reverse transcription-polymerase chain reaction method. Morphometric analysis of the WAT of Zucker fatty rats treated with FK614 (3.2 mg/kg) and pioglitazone (10 mg/kg) was performed. Glucose transport activity in the isolated soleus muscle of FK614-treated Zucker fatty rats was also investigated. Results: FK614 and pioglitazone both improved glucose tolerance in Zucker fatty rats. FK614 significantly increased the expression levels of acyl CoA oxidase, a PPAR-responsive gene, and adipocyte fatty acid-binding protein (aP2), an adipocyte differentiation marker gene, in epididymal WAT. It also significantly decreased the level of gene expression of tumour necrosis factor-alpha, an insulin resistance-inducing factor in retroperitoneal WAT, as did pioglitazone and rosiglitazone. FK614 and pioglitazone both significantly increased the total number of adipocytes and decreased their average size in WAT, mainly by increasing the number of small adipocytes. Additionally, administration of FK614 to Zucker fatty rats enhanced insulin sensitivity for glucose uptake in the soleus muscle. Conclusion: This study suggests the possibility that FK614 induces adipocyte differentiation in Zucker fatty rats by stimulating PPARgammain vivo, thereby changing the character of WAT and improving insulin sensitivity throughout the body.