FK-614(FK-614) - 药物靶点：PPARγ_专利_临床

概要

基本信息

药物类型

小分子化药

别名

+ [1]

靶点

PPARγ

作用机制

PPARγ激动剂(过氧化物酶体增长因子活化受体γ激动剂)、胰岛素增敏剂

治疗领域

神经系统疾病内分泌与代谢疾病

在研适应症-

非在研适应症

非胰岛素依赖型糖尿病2疱疹后神经痛

原研机构

Astellas Pharma, Inc.

在研机构-

非在研机构

Aestus Therapeutics, Inc.

Astellas Pharma, Inc.

最高研发阶段无进展临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

登录后查看时间轴

结构

分子式C21H23Cl2N3O3S

InChIKeyUYGZODVVDUIDDQ-UHFFFAOYSA-N

CAS号193012-35-0

关联

2

项与 FK-614 相关的临床试验

NCT01318226 / Completed临床2期

A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose, Multicenter, Parallel Group Study to Evaluate the Safety and Analgesic Activity of ATx08-001 When Administered to Subjects With Postherpetic Neuralgia

This is a Phase 2 randomized, double-blind, placebo-controlled, multiple-dose, multicenter, parallel-group study to evaluate the analgesic activity of ATx08-001, a novel selective peroxisome proliferator-activated receptor modulator (SPPARM), in subjects with moderate-to-severe postherpetic neuralgia pain. Eligible subjects will be randomized to receive either placebo or Atx08-001. Study drug will be administered orally twice a day for 7 days. Subjects will be evaluated for neuropathic pain intensity at regular intervals over a 6 hour period on Day 1 following the first dose of study drug. They will then be discharged from the clinic and will complete diary assessments of pain severity twice a day at home. Subjects will be asked to return to the clinic on Day 8 to complete their last set of pain evaluations.

开始日期2011-03-01

申办/合作机构

Aestus Therapeutics, Inc.

[+3]

NCT00036192 / Completed临床2期

A Randomized, Double-Blind, Placebo-Controlled Trial of FK614 in Type 2 Diabetics Inadequately Controlled on a Sulfonylurea

The purpose of the study is to assess the safety and efficacy of FK614 in type 2 diabetic subjects receiving sulfonylurea (SU) monotherapy.

开始日期2002-02-01

申办/合作机构

Astellas Pharma, Inc.

[+1]

100 项与 FK-614 相关的临床结果

登录后查看更多信息

100 项与 FK-614 相关的转化医学

登录后查看更多信息

100 项与 FK-614 相关的专利（医药）

登录后查看更多信息

8

项与 FK-614 相关的文献（医药）

2007-05-01·Diabetes, Obesity and Metabolism2区 · 医学

Mechanism by which a novel non‐thiazolidinedione peroxisome proliferator‐activated receptor γ agonist, FK614, ameliorates insulin resistance in Zucker fatty rats

2区 · 医学

Article

作者: S. Mutoh ; J. Hirosumi ; I. Kawamura ; J. Seki ; C. Kimura ; S. Takakura ; T. Manda ; S. Takeshita ; H. Minoura

Aim: The aim of this study was to examine the mechanism by which a novel non‐thiazolidinedione (TZD) peroxisome proliferator‐activated receptor (PPAR) γ agonist, FK614, ameliorates insulin resistance in Zucker fatty rats.Methods: FK614 (1, 3.2 or 10 mg/kg) and a TZD PPARγ 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 PPARγ 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‐α, 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 PPARγin vivo, thereby changing the character of WAT and improving insulin sensitivity throughout the body.

2006-08-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

A Selective Peroxisome Proliferator-Activated Receptor γ Modulator with Distinct Fat Cell Regulation Properties

3区 · 医学

Article

作者: Fujimura, Takao ; Sakuma, Hiroyuki ; Oe, Tomoya ; Mutoh, Seitaro ; Aramori, Ichiro ; Takata, Yoko ; Kimura, Chiaki

Adipogenesis is an important process for the improvement of insulin resistance by peroxisome proliferator-activated receptor (PPAR) gamma agonists, such as rosiglitazone and pioglitazone. FK614 [3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3-Hbenzimidazole-5-carboxamide] is a structurally novel class of PPARgamma agonist that improves insulin sensitivity in animal models of type 2 diabetes. Herein, we characterize FK614, a selective PPARgamma modulator (SPPARM) with differential properties affecting the regulation of fat cell function. FK614 behaves as a partial agonist in inducing the interaction of PPARgamma with both transcriptional coactivators, cAMP response element-binding protein-binding protein and steroid receptor coactivator-1, but as a full agonist with both PPAR-binding protein and PPAR-interacting protein, which are required for PPARgamma-mediated adipogenesis. In the differentiating 3T3-L1 adipocytes, the levels of adipose fatty acid-binding protein (aP2) mRNA expression and triglyceride accumulation induced by FK614 were as efficacious as those of rosiglitazone and pioglitazone. In contrast, the effect of FK614 on aP2 gene expression in mature adipocytes was less than that of the other PPARgamma agonists. Furthermore, the long-term treatment of mature adipocytes with rosiglitazone and pioglitazone reduced the expression of phosphodiesterase 3B, the down-regulation of which has an important role in the development of insulin resistance; however, FK614 had no such effect in mature adipocytes. Thus, FK614 behaves as an SPPARM with differential effects on the activation of PPARgamma at each stage of adipocyte differentiation. The stage-dependent selectivity of FK614 may contribute to its enhanced insulin sensitization in differentiating adipocytes and to reduced insulin resistance at the stage of adipocyte hypertrophy.

2006-01-01·Biological and Pharmaceutical Bulletin4区 · 医学

Unique Properties of Coactivator Recruitment Caused by Differential Binding of FK614, an Anti-diabetic Agent, to Peroxisome Proliferator-Activated Receptor .GAMMA.

4区 · 医学

Article

作者: Mutoh, Seitaro ; Sakuma, Hiroyuki ; Fujimura, Takao ; Ohkubo-Suzuki, Akiko ; Aramori, Ichiro

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.

100 项与 FK-614 相关的药物交易

登录后查看更多信息