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Pirfenidone

现货
Catalog No.
B2288
TGF-β产生的抑制剂
组合的产品项目
规格价格库存 数量
100mg
¥ 630.00
现货
500mg
¥ 1,050.00
现货
1g
¥ 1,620.00
现货
10mM (in 1mL DMSO)
¥ 550.00
现货

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Background

Pirfenidone,an oral antifibrotic agent, has a broad-spectrum of antifibroticand anti-inflammatory effects. Pirfenidonehas beneficial effects for the treatment of certain fibrotic diseases, and is under clinical trials in patients with idiopathic pulmonary fibrosis.

In vitro: In RAW264.7 cells, Pirfenidone (< 300 μg/mL) suppressed the proinflammatory cytokine tumor necrosis factor-α (TNF-α) through a translational mechanism, which was independent of activation of the mitogen-activated protein kinase (MAPK)2, p38 MAP kinase, and c-Jun N-terminal kinase (JNK)[1]. In LN-18, T98G, LNT-229 and LN-308 cell lines, Pirfenidone (< 10 mM) reduced glioma cell density in a concentration-dependent manner. In CCL-64 cells, Pirfenidone (< 5 mM) reduced TGF-β bioactivity by affecting TGF-β2 mRNA expression and processing of pro-TGF-β. Pirfenidone (< 8.3 mM) inhibited the activity of recombinant furin and downregulated the expression of MMP-11 in a dose-dependent manner in LN-308 cells[2].In cultured myometrial and leiomyoma smooth muscle cells, pirfenidone inhibited serum-stimulated increases in DNA synthesis and cell proliferation in a dose-dependent manner[3].

In vivo: In animals, pirfenidone treatment significantly decreased gene expression of collagens I, III and IV, transforming growth factor β-1, Smad-7, TIMP-1 and PAI-1 [4]. Pirfenidone at a dose of 30 mg/kg/day t.i.d. attenuated the bleomycin-induced pulmonary fibrosi. Pirfenidone (30, 100 mg/kg/day t.i.d) suppressed lung inflammatory edema and pulmonary fibrosis. Pirfenidone suppressed the bleomycin-induced increase in lung interleukin (IL)-1β, IL-6, IL-12\p40 and monocyte chemoattractant protein (MCP)-1 levels and prevented the bleomycin-induced decrease in lung interferon (IFN)-γ levels. Furthermore, pirfenidone suppressed elevation of lung basic-fibroblast growth factor (bFGF), transforming growth factor (TGF)-β1 levels, lung stroma cell derived factor (SDF)-1α and IL-18[5].

Pirfenidoneat (250 mg/kg) potently inhibited the production of the proinflammatory cytokines, TNF-α, interferon-gamma, and interleukin-6, but enhanced the production of the anti-inflammatory cytokine, interleukin-10 in mice [1]. Pirfenidone (250 mg/kg/day) ameliorated cyclosporine-induced fibrosis by about 50% and improved CsA-induced decrease in creatinine clearance. PFD treatment also decreased the TGF-β1 protein expression by 80% in salt-depleted Sprague-Dawley rats [6]. Pirfenidone (400 mg/kg/day) inhibited heat shock protein 47-positive cells and myofibroblasts, the principal cells responsible for the accumulation and deposition of extracellular matrix seen in pulmonary fibrosis in ICR mice intravenously injected with bleomycin [7].

In rats treated with dimethylnitrosamine (10 mg/kg) for 5 weeks, 0.5% pirfenidonereduced the degree of liver injury. Administration of pirfenidone(0.5%, liquid diet)downregulated the elevated levels of those transcripts by 50-60%, and this was associated with a 70% reduction in collagen deposition[8].

Clinical Trials: Pirfenidone is a promising agent for individuals with overt diabetic nephropathy. In the pirfenidone 1200-mg/d group, the mean eGFR increased (+3.3 ± 8.5 ml/min per 1.73 m2) while the mean eGFR decreased in the placebo group (2.2 ± 4.8 ml/min per 1.73 m2;P= 0.026). In the pirfenidone 2400-mg/d group, the dropout rate was high (11 of 25) and the change in eGFR was not significantly different from placebo (1.9 ± 6.7 ml/min per 1.73 m2)[9].

Pirfenidone has entered three Phase III, randomized,double-blind, placebo-controlledstudies in patients withidiopathic pulmonary fibrosis(IPF)[10,11]. In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points and a relative increase of 132.5% in the proportion of patients with no decline in FVC (P < 0.001). Pirfenidonealso reduced the decline in the 6-minute walk distance (P = 0.04) and improved progression-free survival (P < 0.001). The most common adverse events were gastrointestinal and skin-related diseases [11].

References:
[1].  Nakazato H, Oku H, Yamane S, et al. A novel anti-fibrotic agent pirfenidone suppresses tumor necrosis factor-α at the translational level[J]. European journal of pharmacology, 2002, 446(1): 177-185.
[2].  Burghardt I, Tritschler F, Opitz C A, et al. Pirfenidone inhibits TGF-β expression in malignant glioma cells[J]. Biochemical and biophysical research communications, 2007, 354(2): 542-547.
[3].  Lee B S, Margolin S B, Nowak R A. Pirfenidone: a novel pharmacological agent that inhibits leiomyoma cell proliferation and collagen production[J]. The Journal of Clinical Endocrinology & Metabolism, 1998, 83(1): 219-223.
[4].  Garca L, Hernández I, Sandoval A, et al. Pirfenidone effectively reverses experimental liver fibrosis[J]. Journal of hepatology, 2002, 37(6): 797-805.
[5].  Oku H, Shimizu T, Kawabata T, et al. Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis[J]. European journal of pharmacology, 2008, 590(1): 400-408.
[6].  Shihab F S, Bennett W M, Yi H, et al. Pirfenidone Treatment Decreases Transforming Growth Factor‐β1 and Matrix Proteins and Ameliorates Fibrosis in Chronic Cyclosporine Nephrotoxicity[J]. American Journal of Transplantation, 2002, 2(2): 111-119.
[7].  Kakugawa T, Mukae H, Hayashi T, et al. Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis[J]. European Respiratory Journal, 2004, 24(1): 57-65.
[8].  Di Sario A, Bendia E, Macarri G, et al. The anti-fibrotic effect of pirfenidone in rat liver fibrosis is mediated by downregulation of procollagen α1 (I), TIMP-1 and MMP-2[J]. Digestive and liver disease, 2004, 36(11): 744-751.
[9].  Sharma K, Ix J H, Mathew A V, et al. Pirfenidone for diabetic nephropathy[J]. Journal of the American Society of Nephrology, 2011, 22(6): 1144-1151.
[10].  Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis[J]. American journal of respiratory and critical care medicine, 2005, 171(9): 1040-1047.
[11].  King Jr T E, Bradford W Z, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis[J]. New England Journal of Medicine, 2014, 370(22): 2083-2092.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt185.22
Cas No.53179-13-8
FormulaC12H11NO
Solubility≥38.4 mg/mL in DMSO, ≥7.68 mg/mL in H2O with gentle warming, ≥36 mg/mL in EtOH
Chemical Name5-methyl-1-phenylpyridin-2-one
SDFDownload SDF
Canonical SMILESCC1=CN(C(=O)C=C1)C2=CC=CC=C2
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

细胞实验 [1]:

细胞系

LN-308细胞和CCL-64细胞

制备方法

在DMSO中的溶解度大于9.3 mg/mL。若配制更高浓度的溶液,一般步骤如下:请将试管置于37 °C加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20 °C可放置数月。

反应条件

1 ~ 10 mM

实验结果

在LN-308细胞中,Pirfenidone (< 10 mM) 呈剂量依赖性地减少胶质瘤细胞数量。同时,Pirfenidone (< 8.3 mM) 也呈剂量依赖性地抑制重组furin蛋白酶活性并下调MMP-11表达。在CCL-64细胞中,Pirfenidone (< 5 mM) 下调TGF-β2 mRNA表达并影响pro-TGF-β加工,从而抑制TGF-β生物活性。

动物实验 [2]:

动物模型

SD大鼠

给药剂量

250 mg/kg/day;口服给药

实验结果

在接受低盐饮食的SD大鼠中,250 mg/kg/day Pirfenidone使环孢菌素诱导的纤维化减少了约50%,同时,使TGF-β1蛋白表达降低了80%。上述结果表明,Pirfenidone可以缓解肾纤维化并减少基质沉积。

注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1]. Burghardt I, Tritschler F, Opitz C A, et al. Pirfenidone inhibits TGF-β expression in malignant glioma cells[J]. Biochemical and biophysical research communications, 2007, 354(2): 542-547.

[2]. Shihab F S, Bennett W M, Yi H, et al. Pirfenidone Treatment Decreases Transforming Growth Factor‐β1 and Matrix Proteins and Ameliorates Fibrosis in Chronic Cyclosporine Nephrotoxicity[J]. American Journal of Transplantation, 2002, 2(2): 111-119.

质量控制

化学结构

Pirfenidone