Synthesis and biological evaluation of the pirfenidone derivatives as antifibrotic agents

Ma, Zhen; Pan, Yani; Huang, Wenhai; Yang, Yan; Wang, Zunyuan; Li, Qin; Zhao, Yin; Zhang, Xinyue; Shen, Zhengrong

doi:10.1016/j.bmcl.2013.11.038

Cited by 22 publications

(16 citation statements)

References 13 publications

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“…MAPK signaling coordinates numerous cell responses by activating substrate proteins involved in transcription, translation, and cell processes such as proliferation, migration, apoptosis, and structural cytoskeletal changes [59]. Previous studies of PFD effects on MAPK signaling report conflicting findings [40,[60][61][62][63][64][65][66][67][68] . However, there is strong evidence for p38 as a primary effector of PFD function.…”

Section: Discussionmentioning

confidence: 99%

Pirfenidone reduces profibrotic responses in human dermal myofibroblasts, in vitro

Hall

Wells

Leung

2018

Laboratory Investigation

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Pirfenidone (PFD) is a synthetic small molecule inhibitor with demonstrated anti-inflammatory and antifibrotic properties in vitro and in vivo. The exact mechanism(s) of PFD action remain unclear, due in part to the broad effects of this drug on the complex processes involved in inflammation and fibrosis. While PFD is FDA-approved for the treatment of idiopathic pulmonary fibrosis, the efficacy of this compound for the treatment of dermal fibrosis has not yet been fully characterized. Dermal fibrosis is the pathological formation of excess fibrous connective tissue of the skin, usually the result of traumatic cutaneous injury. Fibroproliferative scarring, caused by delayed wound healing and prolonged inflammation, remains a major clinical concern with considerable morbidity. Despite efforts to identify a therapeutic that targets the fibrotic pathways involved in wound healing to mitigate scar formation, no satisfactory dermal antifibrotic has yet been identified. We aim to better elucidate the antifibrotic mechanism(s) of PFD activity using an in vitro model of dermal fibrosis. Briefly, cultured human dermal fibroblasts were stimulated with TGF-β1 to induce differentiation into profibrotic myofibroblast cells. A dose-dependent reduction in cellular proliferation and migration was observed in TGF-β1-stimulated cells when treated with PFD. We observed a clear inhibition in the development of essential myofibroblast mechanoregulatory machinery, including contractile F-actin stress fibers containing α-SMA and large super-mature focal adhesions. PFD treatment significantly reduced protein levels of major ECM components type I and type III collagen. PFD targeted the p38 MAPK signaling pathway and mitigated profibrotic gene expression profiles. This in vitro data promotes PFD as a potential therapeutic agent for the treatment of dermal fibrosis.

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Section: Discussionmentioning

confidence: 99%

Pirfenidone reduces profibrotic responses in human dermal myofibroblasts, in vitro

Hall

Wells

Leung

2018

Laboratory Investigation

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“…Several studies have reported that an increase in TGF-␤ production leads to cardiac fibrosis; conversely, inhibition of TGF-␤ suppresses fibrosis development in many experimental models (27). Recent studies reported that PFD blocked TGF-␤-induced Smad signaling, but not MAPK signaling, in the human retinal pigment epithelial cell line arising retinal pigment epithelia-19 (4) and exerted antifibrotic effects via the inhibition of TGF-␤-induced p38 phosphorylation in the human lung fibroblast cell line MRC-5 (5,16). These results indicate that PFD might target different signaling pathways in different cell types.…”

Section: Discussionmentioning

confidence: 99%

Pirfenidone exhibits cardioprotective effects by regulating myocardial fibrosis and vascular permeability in pressure-overloaded hearts

Yamagami

Oka

Wang

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Although cardiac fibrosis causes heart failure, its molecular mechanisms remain elusive. In this study, we investigated the mechanisms of cardiac fibrosis and examined the effects of the antifibrotic drug pirfenidone (PFD) on chronic heart failure. To understand the responsible mechanisms, we generated an in vivo pressure-overloaded heart failure model via transverse aortic constriction (TAC) and examined the effects of PFD on chronic-phase cardiac fibrosis and function. In the vehicle group, contractile dysfunction and left ventricle fibrosis progressed further from 4 to 8 wk after TAC but were prevented by PFD treatment beginning 4 wk after TAC. We isolated cardiac fibroblasts and vascular endothelial cells from the left ventricles of adult male mice and investigated the cell-type-specific effects of PFD. Transforming growth factor-β induced upregulated collagen 1 expression via p38 phosphorylation and downregulated claudin 5 (Cldn5) expression in cardiac fibroblasts and endothelial cells, respectively; both processes were inhibited by PFD. Moreover, PFD inhibited changes in the collagen 1 and Cldn5 expression levels, resulting in reduced fibrosis and serum albumin leakage into the interstitial space during the chronic phase in TAC hearts. In conclusion, PFD inhibited cardiac fibrosis by suppressing both collagen expression and the increased vascular permeability induced by pressure overload.

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“…In response to recent evidence suggesting p38 MAPK pathway inhibition is the mechanism of action of pirfenidone (Li et al, 2016; Ma et al, 2014; Neri et al, 2016), we stimulated IPF lung fibroblasts with TGFβ for 30 min in the presence of pirfenidone and our inactive mimics (Fig. 4B).…”

Section: Resultsmentioning

confidence: 99%

“…1) has led to debate about the potential for pirfenidone to bind to a selective target or pocket, and has stimulated an alternative hypothesis that pirfenidone simply works as a free radical scavenging antioxidant (Mitani et al, 2008; Salazar-Montes et al, 2008). Some very recent work has suggested pirfenidone is an inhibitor of the p38 mitogen-activated protein kinase (p38 MAPK) pathway (Li et al, 2016; Ma et al, 2014; Neri et al, 2016; Yin et al, 2016). A major barrier to further delineating pirfenidone’s mechanism of action is the absence of structurally similar compounds which lack antifibrotic efficacy.…”

Section: Introductionmentioning

confidence: 99%

Phenylpyrrolidine structural mimics of pirfenidone lacking antifibrotic activity: A new tool for mechanism of action studies

Haak

Girtman

Ali

et al. 2017

European Journal of Pharmacology

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Pirfenidone recently received FDA approval as one of the first two drugs designed to treat idiopathic pulmonary fibrosis. While the clinical data continues to support the efficacy of pirfenidone, the specific molecular mechanism of action of this drug has not been fully defined. From a chemical perspective the comparatively simple and lipophilic structure of pirfenidone combined with its administration at high doses, both experimentally and clinically, complicates some of the basic tenants of drug action and drug design. Our objective here was to identify a commercially available structural mimic of pirfenidone which retains key aspects of its physical chemical properties but does not display any of its antifibrotic effects. We tested these molecules using lung fibroblasts derived from patients with idiopathic pulmonary fibrosis and found phenylpyrrolidine based analogs of pirfenidone that were non-toxic and lacked antifibrotic activity even when applied at millimolar concentrations. Based on our findings, these molecules represent pharmacological tools for future studies delineating pirfenidone’s mechanism of action.

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Synthesis and biological evaluation of the pirfenidone derivatives as antifibrotic agents

Cited by 22 publications

References 13 publications

Pirfenidone reduces profibrotic responses in human dermal myofibroblasts, in vitro

Pirfenidone reduces profibrotic responses in human dermal myofibroblasts, in vitro

Pirfenidone exhibits cardioprotective effects by regulating myocardial fibrosis and vascular permeability in pressure-overloaded hearts

Phenylpyrrolidine structural mimics of pirfenidone lacking antifibrotic activity: A new tool for mechanism of action studies

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