Idiopathic pulmonary fibrosis (IPF) is a typical chronic fibrosing interstitial pneumonia characterized by progressive worsening of dyspnea and lung function with a poor prognosis. With a median survival of 3 to 5 years and a 5-year survival rate of approximately 20%, IPF is an ultimately fatal disease which is considered more lethal than most of the malignant cancers. The pathogenesis of IPF implicated a variety of cellular processes, signaling pathways, and genetics. However, the precision mechanisms of the disorder are poorly understood. Pirfenidone is the first orally administered drug that has orphan designation for the treatment of IPF. It is generally thought to be a multiple-targets drug with antifibrotic, anti-inflammatory, antioxidative stress and antiproliferative effects. Beneficial effects have been shown for pirfenidone in the fibrotic disease, including pulmonary, liver, renal, and cardiac muscle fibrosis. Unfortunately, some side effects including gastrointestinal upset, fatigue and photosensitivity have been observed in clinical practices for pirfenidone. It was speculated that these adverse symptoms might be attributed to the requirement for high therapeutically effective doses of pirfenidone. Therefore, considerable efforts have been made towards the modification of pirfenidone in order to increase the antifibrotic activity. Novel pirfenidone derivatives were designed, synthesized and evaluated for their antifibrotic activity by our group. These compounds showed the remarkable inhibition on cell proliferation compared with pirfenidone in vitro. The antifibrotic activity of compound 8d as the ideal candidate of the novel pirfenidone derivatives in in vivo is reported. In this study, 8d effectively inhibits TGF-β1-induced fibroblast differentiation through inactivation of p38 and Smad3 phosphorylation in vitro. Furthermore, 8d treatment of rats with bleomycin-induced pulmonary fibrosis also shows significantly attenuation of fibrosis. Our findings indicate that 8d downregulates the levels of TGF-β1, p38 MAPK and α-SMA protein expression, and markedly inhibit fibroblast activation and collagen deposition in lung tissues of pulmonary fibrosis rats. We demonstrate that this novel pirfenidone derivative attenuates fibrosis probably by inhibiting the key cytokine TGF-β1 and phosphorylated p38 MAPK. The results of the present study suggest that 8d might be a potent agent with antifibrotic property for treatment of IPF.

Novel pirfenidone derivatives: Potent antifibrotic agents

254th National Meeting (2017)

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