Discovery of novel capsaicin analogs as TRPV1 inhibitors for the treatment of idiopathic pulmonary fibrosis

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2024-12-30 DOI:10.1016/j.ejmech.2024.117229

Yu Cao , Yongju Wen , Zongyuan Zhou , Ruiying Xi , Wen Shuai , Jichao Zhang , Apichart Suksamrarn , Guolin Zhang , Xiao-xia Lu , Fei Wang

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引用次数: 0

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease for which few drugs are available in clinical practice. Here, we identified novel capsaicin analogs by combining in-house chemical library screening and further structural optimization. (E)-1-(3,4-dihydroxyphenyl)-7-phenylhept-1-en-3-one (Compound 14) was found to be the most potent in inhibiting TGF-β-induced collagen accumulation, proliferation and migration in fibroblast cells. Furthermore, compound 14 (IC₅₀ = 0.51 ± 0.06 μM) showed over 100-fold increasing antifibrotic activity compared to capsaicin (IC₅₀ = 53.71 ± 4.78 μM). Notably, compound 14 could target TRPV1, thereby affecting the expression of the fibrosis markers Collagen Ⅰ and α-SMA by inhibiting the TGF-β/Smads and MAPK pathways to exert antifibrotic activity in vitro. Compound 14 significantly inhibited collagen deposition in lung tissues, ameliorated alveolar structures, and increased survival rates in mice with bleomycin-induced pulmonary fibrosis. In addition, compound 14 possessed lower cytotoxicity (compared to nitedanib) and no toxicity in mice. Overall, compound 14 promise as a potential drug candidate for the treatment of IPF.

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发现新型辣椒素类似物作为TRPV1抑制剂治疗特发性肺纤维化

特发性肺纤维化（IPF）是一种进行性和致死性间质性肺疾病，临床治疗药物很少。在这里，我们通过内部化学文库筛选和进一步的结构优化，确定了新的辣椒素类似物。(E)-1-（3,4-二羟基苯基）-7-苯基庚-1-en-3-one（化合物14）对TGF-β-诱导的成纤维细胞中胶原的积累、增殖和迁移的抑制作用最强。化合物14的抗纤维化活性（IC50 = 0.51±0.06 μM）是辣椒素（IC50 = 53.71±4.78 μM）的100倍以上。值得注意的是，化合物14可以靶向TRPV1，通过抑制TGF-β/Smads和MAPK通路，影响纤维化标志物胶原Ⅰ和α-SMA的表达，从而在体外发挥抗纤维化活性。化合物14显著抑制肺组织胶原沉积，改善肺泡结构，提高博莱霉素诱导肺纤维化小鼠的存活率。此外，化合物14具有较低的细胞毒性（与尼达尼布相比），对小鼠无毒性。总之，化合物14有望成为治疗IPF的潜在候选药物。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.