Synthesis and structure-activity relationships of pirfenidone derivatives as anti-fibrosis agents in vitro

Xiufang Shi; Zhenqiang Yu; Chaoran Zhu; Linlin Jiang; Nanqi Geng; Xingting Fan; Zhanghui Guan; Xiang Lu

doi:10.1039/d1md00403d

Synthesis and structure-activity relationships of pirfenidone derivatives as anti-fibrosis agents in vitro

RSC Med Chem. 2022 Apr 1;13(5):610-621. doi: 10.1039/d1md00403d. eCollection 2022 May 25.

Authors

Xiufang Shi^{1

2

3}, Zhenqiang Yu^{1

2

3}, Chaoran Zhu^{1

2

3}, Linlin Jiang^{1

2

3}, Nanqi Geng^{1

2

3}, Xingting Fan^{1

2

3}, Zhanghui Guan^{1

2

3}, Xiang Lu^{1

2

3}

Affiliations

¹ Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases Henan Province China.
² Collaborative Innovation Center of New Drug Research and Safety Evaluation Henan Province Zhengzhou China.
³ School of Pharmaceutical Sciences, Zhengzhou University Zhengzhou 450001 China yxyxianglu@zzu.edu.cn.

Abstract

Pirfenidone (PFD) was the first approved drug by FDA for the treatment of idiopathic pulmonary fibrosis (IPF). However, the rapid metabolism of 5-methyl of PFD increases the risk of side effects in clinics. Thus, in this paper, a common practice that a stable amide bond linking various groups used to replace 5-methyl of PFD in medicinal chemistry was applied, and total 18 PFD derivatives were synthesized. All compounds were investigated for their antiproliferation activities against NIH3T3 cells and the structure-activity relationships of the target compounds were also discussed. Among them, YZQ17 possessed potent antiproliferation activity compared to PFD and better potency in inhibiting TGF-β-induced migration of NIH3T3 cells at a much lower concentration than that of PFD. In addition, YZQ17 dramatically inhibited the expression levels of fibrotic markers α-SMA, collagen I, and fibronectin. Moreover, further mechanistic studies confirmed that YZQ17 exhibited this considerable anti-fibrosis activity via the TGF-β/Smad2/3 dependent pathway. Finally, the results of human and rat liver microsomes assay in vitro and pharmacokinetic assay in rats confirmed that YZQ17 showed better pharmacokinetics than that of PFD. Collectively, the preliminary study of PFD derivatives modified by the amide group indicated that YZQ17 could be regarded as a lead compound for further investigation and optimization.