Description
Until recently, IPF therapy consisted of a combination of corticosteroids
and immunosuppressive agents (azathioprine and cyclophosphamide)
to target the inflammation that was believed to be the pathogenic
stimulus.Since IPF is now considered to be predominantly a disorder of
fibroproliferation, agents that intervene in fibrogenesis have moved
to the forefront of treatment options. With demonstrated efficacy in a
bleomycin-induced lung fibrosis animal model, pirfenidone has been
developed and launched as an approved therapy for IPF. Its antifibrotic activity is derived from the inhibition of p38 MAP kinase that is
upstream of transforming growth factor-β (TGF-β), a cytokine implicated
in the stimulation of collagen synthesis and the inhibition of its
degradation. Pirfenidone also inhibits the expression of TNF-α, IL-1,
and ICAM-1, so it possesses the dual benefit of an anti-inflammatory and
antifibrotic agent. This relatively simplistic drug is constructed by the copper-catalyzed reaction of 5-methyl-2(1H)-pyridinone with bromo- or chlorobenzene.
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Chemical Properties
Off-White Solid
Originator
Marnac (United States)
Definition
ChEBI: A pyridone that is 2-pyridone substituted at positions 1 and 5 by phenyl and methyl groups respectively. An anti-inflammatory drug used for the treatment of idiopathic pulmonary fibrosis.
General Description
Pirfenidone?(5-methyl-1-phenyl-2-[1H]-pyridone) is a synthetic derivative of pyridine.
Biological Activity
Antifibrotic agent, effective in models of pulmonary and lung fibrosis. Inhibits collagen production and fibroblast proliferation. Regulates cytokine levels following oral administration in vivo . Potent scavenger of free radicals and inhibitor of lipid peroxidation.
Biochem/physiol Actions
Pirfenidone inhibits collagen production and fibroblast proliferation. It has shown antifibrotic and anti-inflammatory properties in variety of animal models of pulmonary fibrosis, and in clinical trials.
Synthesis
Pirfenidone
may inhibit collagen synthesis, down-regulate production of
multiple cytokines, and block fibroblast proliferation and stimulation in response to cytokines. Pirfenidone was
prepared via a two step sequence as detailed in the scheme.2-Amino-5-methylpyridine (91) was converted to pyridone
92 by reaction with sulfuric acid and sodium nitrate at
low temperature in 73% yield. Condensation of 5-methyl-2-
(1H)-pyridone (92) with iodobenzene (93) in the presence of
K2CO3 and CuCl at reflux gave pirfenidone (XIII) in 85%
yield.
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].
References
1) Kehrer and Margolin (1997),?Pirfenidone diminishes cyclophosphamide-induced lung fibrosis in mice; Toxicol.Lett.,?90?125
2) Iyet?et al.?(1999),?Effects of pirfenidone on procollagen gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis; J.Pharmacol.Exp.Ther.,?289?211
3) Xie?et al.?(2002),?Upregulation of RGS2: a new mechanism for pirfenidone amelioration of pulmonary fibrosis; Respir.Res.,?17?103
4) Li?et al.?(2016),?Oral pirfenidone protects against fibrosis by inhibiting fibroblast proliferation and TGF-b signaling in a murine colitis model;?Biochem.Pharmacol.,?117?57
5) Nakazato?et al.?(2002),?A novel anti-fibrotic agent pirfenidone suppresses tumor necrosis factor-alpha at the translational level, Eur.J.Pharmacol.?446?177
6) Misra and Rabideau (2000),?Pirfenidone inhibits NADPH-dependent microsomal lipid peroxidation and scavenges hydroxyl radicals, Mol.Cell Biochem.?204?119
7) Canestaro?et al.?(2016),?Drug Treatment of Idiopathic Pulmonary Fibrosis: Systemic Review and Network Meta-Analysis; Chest,?149?756
