Pharmacological characteristics of a novel nonthiazolidinedione insulin sensitizer, FK614

Minoura, Hideaki; Takeshita, S; Ita, Makoto; Hirosumi, Jiro; Mabuchi, Miyuki; Kawamura, Ikuo; Nakajima, Satoko; Numata, Osamu; Kayakiri, Hiroshi; Oku, Teruo; Ohkubo-Suzuki, Akiko; Fukagawa, Masafumi; Kojo, Hitoshi; Hanioka, Kenichi; Yamasaki, Noritsugu; Imoto, T.; Kobayashi, Yoshinori; Mutoh, Seitaro

doi:10.1016/j.ejphar.2004.04.038

Cited by 76 publications

(63 citation statements)

References 31 publications

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“…1) substantially improves hyperglycemia, hyper-triglyceridemia, hyperinsulinemia, and disorder of glucose tolerance in genetically obese and diabetic animal models (12). The anti-diabetic activity of FK614 was comparable to that of rosiglitazone and pioglitazone.…”

Section: Introductionmentioning

confidence: 78%

“…In a previous report we demonstrated that FK614 is a partial agonist, activating PPARγ-mediated transcription in a reporter gene assay using the peroxisome prolifera-tor-activated response element (PPRE) from the acylcoenzyme A (acyl-CoA) oxidase gene and has no effect on PPARα transactivation (12). In order to clarify that the anti-diabetic effect elicited by FK614 in vivo is due to the activation of PPARγ, a systematic examination of its activity and selectivity on all PPARα-, PPARδ-, and PPARγ-mediated transactivation was performed in a cell based reporter gene assay utilizing a GAL4-fusion construct.…”

Section: Fk614 Acts As a Selective Partial Agonist For Pparγ In A Galmentioning

confidence: 99%

“…Although FK614 was originally identified in an in vivo animal model, subsequent in vitro studies showed this compound induced PPARγ-mediated transcription in a reporter gene assay. Despite FK614 producing a robust improvement in insulin resistance in vivo, this compound appeared to be a partial agonist of PPARγ mediated transactivation in vitro (12).…”

Section: Introductionmentioning

confidence: 99%

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FK614, a Novel Peroxisome Proliferator-Activated Receptor γ Modulator, Induces Differential Transactivation Through a Unique Ligand-Specific Interaction With Transcriptional Coactivators

et al. 2005

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Abstract. Peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ agonist that demonstrates potent anti-diabetic activity in vivo. Herein, we describe that FK614 is a selective PPARγ 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 PPARγ as effectively as rosiglitazone and pioglitazone, but can also differentially induce a ligand specific interaction of PPARγ with coactivators. The amount of CBP (CREBbinding 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-1α (PPARγ coactivator-1α) recruitment as these compounds. As a consequence of these ligand-specific differences in the strength of ligand-type specific interactions of PPARγ 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 PPARγ modulator whose pharmacological properties are distinct from rosiglitazone and pioglitazone.

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Section: Introductionmentioning

confidence: 78%

Section: Fk614 Acts As a Selective Partial Agonist For Pparγ In A Galmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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FK614, a Novel Peroxisome Proliferator-Activated Receptor γ Modulator, Induces Differential Transactivation Through a Unique Ligand-Specific Interaction With Transcriptional Coactivators

et al. 2005

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“…Recently, benzimidazole derivatives have been found to be active on several targets useful for the development of antidiabetic therapeutics, e.g. inhibitors of dipeptidyl peptidase IV 12 and activators of peroxisome proliferator-activated receptor- (PPAR-) 13,14 .…”

Section: Introductionmentioning

confidence: 99%

“…H nuclear magnetic resonance (NMR) and 13 C NMR spectra were recorded on a Varian Gemini 200 MHz and an Avance 300 MHz spectrometer in CDCl 3 and DMSO-d 6 using tetramethylsilane (TMS) as internal standard. All chemical shifts are reported as  (ppm) values.…”

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confidence: 99%

New antihyperglycemic, α-glucosidase inhibitory, and cytotoxic derivatives of benzimidazoles

Jaladi

Tiwari

Ali

et al. 2009

Journal of Enzyme Inhibition and Medicinal Chemistry

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Nuclear Hormone Receptor Medicinal Chemistry

Cheng

Kick

Mukherjee

2010

Burger's Medicinal Chemistry and Drug Discovery

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This chapter will be focused on recent advances in the medicinal chemistry of agonist, antagonist, and modulator ligands of selected nuclear hormone receptors (NHRs) that are of special interest in the metabolic diseases therapeutic area (diabetes, obesity and dyslipidemia/atherosclerosis). These NHRs include established biological targets such as the peroxisome proliferator‐activated receptors (PPARs), the liver X receptors (LXRs), and the farnesoid X receptors (FXRs), for which ligands have reached either clinical development or have been approved for clinical usage. Other more recent targets of interest to metabolic diseases include HNF and Rev‐erb.

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Pharmacological characteristics of a novel nonthiazolidinedione insulin sensitizer, FK614

Cited by 76 publications

References 31 publications

FK614, a Novel Peroxisome Proliferator-Activated Receptor γ Modulator, Induces Differential Transactivation Through a Unique Ligand-Specific Interaction With Transcriptional Coactivators

FK614, a Novel Peroxisome Proliferator-Activated Receptor γ Modulator, Induces Differential Transactivation Through a Unique Ligand-Specific Interaction With Transcriptional Coactivators

New antihyperglycemic, α-glucosidase inhibitory, and cytotoxic derivatives of benzimidazoles

Nuclear Hormone Receptor Medicinal Chemistry

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