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Discovery of 4-cyclopropyl-3-(2-((1-cyclopropyl-1H-pyrazol-4-yl) amino) quinazolin-6-yl)-N-(3-(trifluoromethyl) phenyl) benzamides as potent discoidin domain receptor inhibitors for the treatment of idiopathic pulmonary fibrosis

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1943-1962页

作者： Qi Wang Bixi Tang Dandan Sun Ying Dong Yinchun Ji Huanyu Shi Liwei Zhou Yueyue Yang Menglan Luo Qian Tan Lin Chen Yue Dong Cong Li Rongrong Xie Yi Zang Jingkang Shen Bing Xiong Jia Li Danqi Chen Department of Medicinal Chemistry Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Division of Anti-tumor Pharmacology State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Center for Supramolecular Chemistry and Catalysis and Department of Chemistry College of SciencesShanghai UniversityShanghai 200444China Department of Pharmacology School of PharmacyFudan UniversityShanghai 201203China School of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing 210023China Department of pulmonary and Critical Care Medicine Shanghai Fifth People’s HospitalFudan UniversityShanghai 200240China Department of Chemistry College of SciencesShanghai UniversityShanghai 200444China School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUCASHangzhou 310024China

idiopathic pulmonary fibrosis(IPF)is a chronic fatal lung disease with a median survival time of 3–5 *** diagnosis,limited clinical therapy and high mortality together indicate that the development of effective therapeutics for IPF is an urgent *** recent years,it was reported that DDRs are potential targets in anti-fibrosis *** on previous work we carried out further structure modifications and led to a more selective inhibitor 47 by averting some fibrosis-unrelated kinases,such as RET,AXL and *** profiling of compound 47 has demonstrated that it has potent DDR1/2 inhibitory activities,low toxicity,good pharmacokinetic properties and reliable in vivo anti-fibrosis ***,we confirmed that discoidin domain receptors are promising drug targets for IPF,and compound 47 would be a promising candidate for further drug development.

关键词： idiopathic pulmonary fibrosis Discoidin domain receptor Kinase Inhibitor Docking

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idiopathic pulmonary fibrosis will increase the risk of lung cancer

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Chinese Medical Journal 2014年第17期127卷 3142-3149页

作者： Li Junyao Yang Ming Li Ping Su Zhenzhong Gao Peng Zhang Jie Department of Respiratory and Critical Care Medicine the Second Affiliated Hospital of Jilin University Changchun Jilin 130041China Centre for Asthma and Respiratory Disease School of Biomedical Sciences and Pharmacy Faculty of Health University of Newcastle and Hunter Medical Research Institute Callaghan New South Wales 2230 Australia Department of Pediatrics the second Affiliated Hospital of Jilin University Changchun Jilin 130041China

Objective To review the studies investigating the increased risk of lung cancer in patients with idiopathic pulmonary fibrosis （IPF）.Data sources Data cited in this review were obtained mainly from PubMed and Medline from 1999 to 2013 and highly regarded older publications were also *** selection We identified,retrieved and reviewed the information on the frequency,risk factors,anatomical features,histological types,clinical manifestations,computed tomography findings and underlying mechanisms of lung cancer in IPF *** The prevalence rates of lung cancer in patients with IPF （4.8％ to 48％） are much higher than patients without IPF （2.0％ to 6.4％）.The risk factors for lung cancer in IPF include smoking,male gender,and *** cancers often occur in the peripheral lung zones where fibrotic changes are *** and squamous cell carcinoma are the most common types of lung cancer in patients with *** features of these patients include peripherally located,ill-defined mass mimicking air-space *** underlying mechanisms of the development of lung cancer in patients with IPF have not been fully understood,but may include the inflammatory response,epithelial injury and/or abnormalities,aberrant fibroblast proliferation,epigenetic and genetic changes,reduced cell-to-cell communication,and activation of specific signaling *** These findings suggest that IPF is associated with increased lung cancer *** is necessary to raise the awareness of lung cancer risk in IPF patients among physicians and patients.

关键词： idiopathic pulmonary fibrosis lung cancer prevalence risk factors

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idiopathic pulmonary fibrosis in relation to gene polymorphisms of transforming growth factor-β1 and plasminogen activator inhibitor 1

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Chinese Medical Journal 2011年第13期000卷 1923-1927页

作者： LI Xin-xia LI Ning BAN Cheng-jun ZHU Min XIAO Bai DAI Hua-ping Beijing Key Laboratory of Respiratory and pulmonary Circulation Beijing Institute of Respiratory Medicine Department ofRespiratory and Critical Care Medicine Beijing Chao-YangHospital Capital Medical University Beijing 100020 China Department of Respiratory Medicine Beijing Shijitan HospitalCapital Medical University Beijing 100038 China Department of Respiratory Medicine Beijing Fu 'Xing I~IospitalCapital Medical University Beijing 100038 China

Background idiopathic pulmonary fibrosis （IPF） is a progressive and lethal fibrotic lung disease of unknown etiology. Host susceptibility or genetic factors may be important for the predisposition to it. Transforming growth factor-β1 （TGF-β1 a potent profibrotic cytokine） and plasminogen activator inhibitor 1 （PAl-1） play important roles in the development of pulmonary fibrosis. The objective of the study was to investigate the association between the gene polymorphisms of TGF-β1 869 T〉C and PAl-1 4G/5G and the susceptibility to IPF in Han ethnicity. Methods Polymerase chain reaction （PCR） and restriction fragment length polymorphism were performed to analyse the gene polymorphisms of TGF-β1 in 869T〉C and PAl-1 4G/5G in 85 IPF patients and 85 healthy controls matched in age, gender, race and smoker status. Results There was a significant difference in 869T〉C genotype distribution of TGF-β1 between IPF cases and controls, a significant negative association between TC genotype and the development of IPF （OR=0.508, 95% CI： 0.275-0.941） and a positive association between CC genotype and the development of IPF （OR=1.967, 95% CI： 1.063-3.641）. There was a significant positive association between PAl-1 5G/5G genotype and the development of IPF （OR=0.418, 95% CI： 0.193-0.904）. Conclusions Gene polymorphisms of TGF-β1 in 869T〉Cand PAl-1 4G/5G may affect the susceptibility to IPF in Han ethnicity. Further investigations are needed to confirm these findings and assess their biological significance in the development of the disease in this ethnic population.

关键词： gene polymorphism genetic susceptibility idiopathic pulmonary fibrosis plasminogen activator inhibitor 1 transforming growth factor-beta 1

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MicroRNAs in idiopathic pulmonary fibrosis: involvement in pathogenesis and potential use in diagnosis and therapeutics

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Acta Pharmaceutica Sinica B 2016年第6期6卷 531-539页

作者： Huimin Li Xiaoguang Zhao Hongli Shan Haihai Liang Department of Pharmacology College of Pharmacy Harbin Medical University

MicroRNAs (miRNAs) are a class of phylogenetically conserved, non-coding short RNAs, 19-22 nt in length which suppress protein expression through base-pairing with the 3'-untranslated region of target mRNAs. miRNAs have been found to participate in cell proliferation, differentiation and apoptosis. idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high lethality fibrotic lung disease for which currently there is no effective treatment. Some miRNAs have been reported to be involved in the pathogenesis of pulmonary fibrosis. In this review, we discuss the role of miRNAs in the pathogenesis, diagnosis and treatment of IPF. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND

关键词： idiopathic pulmonary fibrosis MicroPNA Pathogenesis Early diagnosis Therapeutic target lncRNA

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idiopathic pulmonary fibrosis： A Systemic Disease？

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Chinese Medical Journal 2017年第17期130卷 2140-2141页

作者： Luo Man Peng Hong Department of Respiratory Medicine The Second Xiangya Hospital Central South University Changsha Hunan 410011 China Research Unit of Respiratory Disease Central South University Changsha Hunan 410011 China Diagnosis and Treatment Central of Respiratory Disease Central South University Changsha Hunan 410011 China

INTRODUCTIONidiopathic puhnonary fibrosis （IPF） is a specific type of chronic progressive fibrosing interstitial pneumonia associated with a histopathologic pattern of usual interstitial pneumonia. IPF is typically considered to be a lung-limited disorder. Although the primary manifestations of IPF are pulmonary in nature. IPF is increasingly recognized as a systemic disease due to its strong association with comorbiditics and coml）lications.

关键词： idiopathic pulmonary fibrosis Gastroesophageal Reflux Disease Genetics

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Efficacy and safety of Kangxian Huanji Granule as adjunctive treatment in acute exacerbation of idiopathic pulmonary fibrosis:An exploratory randomized controlled trial

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Journal of Integrative Medicine 2023年第6期21卷 543-549页

作者： Jian-sheng Li Hai-long Zhang Wen Guo Lu Wang Dong Zhang Li-min Zhao Miao Zhou Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan&Education Ministry of China Henan Key Laboratory of Chinese Medicine for Respiratory DiseasesHenan University of Chinese MedicineZhengzhou 450046Henan ProvinceChina Respiratory Department the First Affiliated Hospital of Henan University of Chinese MedicineZhengzhou 450000Henan ProvinceChina Department of Respiratory and Critical Care Medicine Henan Provincial People’s HospitalZhengzhou 463599Henan ProvinceChina Respiratory Department the Third Affiliated Hospital of Henan University of Chinese MedicineZhengzhou 450003Henan ProvinceChina

Background:Acute exacerbation of idiopathic pulmonary fibrosis(AE-IPF)is an important occurrence in the natural history of idiopathic pulmonary fibrosis(IPF),associated with high hospitalization rates,high mortality and poor *** present,there is no effective treatment for *** herbal medicine has some advantages in treating IPF,but its utility in AE-IPF is ***:The treatment of AE-IPF with Kangxian Huanji Granule(KXHJ),a compound Chinese herbal medicine,lacks an evidence-based *** study explores the efficacy and safety of KXHJ in patients with ***,setting,participants and interventions:Wedesigned a randomized,double-blind,placebo-controlled,exploratory clinical trial.A total of 80 participants diagnosed with AE-IPF were randomly assigned to receive KXHJ or a matching placebo;the treatment included a 10 g dose,administered twice daily for 4 weeks,in addition to conventional *** were followed up for 12 weeks after the *** outcome measures:The primary endpoints were treatment failure rate and all-cause *** endpoints included the length of hospitalization,overall survival,acute exacerbation rate,intubation rate,the modified British Medical Research Council(mMRC)score,and the St George’s Respiratory Questionnaire for IPF(SGRQ-I)***:The rate of treatment failure at 4 weeks was lower in the intervention groupcompared to the control group(risk ratio[RR]:0.22;95%confidence interval[CI]:0.051 to 0.965,P=0.023).There was no significant difference in all-causemortality at 16 weeks(RR:0.75;95%CI:0.179 to 3.138;P>0.999)or in the acute exacerbation rate during the 12-week follow-up period(RR:0.69;95%CI:0.334 to 1.434;P=0.317).The intervention group had a shorter length of hospitalization than the control group(mean difference[MD]:–3.30 days;95%CI,–6.300 to–0.300;P=0.032).Significant differences in the mean change from baseline in the mMRC(between-group difference:–0.67;

关键词： idiopathic pulmonary fibrosis Acute exacerbation Chinese herbal medicine Integrative medicine Randomized controlled trial

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Targeting PI3K/AKT signaling for treatment of idiopathic pulmonary fibrosis

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Acta Pharmaceutica Sinica B 2022年第1期12卷 18-32页

作者： Jincheng Wang Kaili Hu Xuanyan Cai Bo Yang Qiaojun He Jiajia Wang Qinjie Weng Center for Drug Safety Evaluation and Research College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058 Hangzhou Institute of Innovative Medicine College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058

idiopathic pulmonary fibrosis(IPF) is a chronic progressive fibrotic interstitial pneumonia with unknown causes. The incidence rate increases year by year and the prognosis is poor without ***, phosphatidylinositol 3-kinase(PI3 K)/protein kinase B(PKB/AKT) signaling pathway can be considered as a master regulator for IPF. The contribution of the PI3 K/AKT in fibrotic processes is increasingly prominent, with PI3 K/AKT inhibitors currently under clinical evaluation in IPF. Therefore,PI3 K/AKT represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies. This review epitomizes the progress that is being made in understanding the complex interpretation of the cause of IPF, and demonstrates that PI3 K/AKT can directly participate to the greatest extent in the formation of IPF or cooperate with other pathways to promote the development of fibrosis. We further summarize promising PI3 K/AKT inhibitors with IPF treatment benefits, including inhibitors in clinical trials and pre-clinical studies and natural products, and discuss how these inhibitors mitigate fibrotic progression to explore possible potential agents, which will help to develop effective treatment strategies for IPF in the near future.

关键词： idiopathic pulmonary fibrosis PI3K/AKT signaling Pathogenesis Coagulation cascade Immune activation Fibroblast accumulation Therapeutic target Drug therapy

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Inhalation of taraxasterol loaded mixed micelles for the treatment of idiopathic pulmonary fibrosis

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Chinese Chemical Letters 2024年第8期35卷 475-480页

作者： Tong Zhang Chao Sun Shubin Yang Zimin Cai Sifeng Zhu Wendian Liu Yun Luan Cheng Wang Key Laboratory of Marine Drugs Chinese Ministry of EducationSchool of Medicine and PharmacyOcean University of ChinaQingdao 266003China Central Research Laboratory Department of General Surgerythe Second Hospital of Shandong UniversityJi’nan 250033China Laboratory for Marine Drugs and Bioproducts Pilot National Laboratory for Marine Science and TechnologyQingdao 266237China Orthopedics Dept.1 Rushan people’s hospitalRushan 264500China Department of Cardiology the Second Hospital of Shandong UniversityJi’nan 250033China

idiopathic pulmonary fibrosis(IPF)is a chronic and fatal lung disease characterized by pulmonary inflam-mation,oxidative stress,and excessive extracellular matrix(ECM)*** anti-fibrotic drugs for IPF treatment in the clinic lack selectivity and demonstrate unsatisfactory efficacy,highlighting the urgent necessity for a novel therapeutic ***(TA),which has biological activities against lung injury induced by various factors,is a potential anti-IPF drug due to its anti-inflammatory,antiox-idant and lung-protective ***,the protective effect of TA on IPF has not been confirmed,and its clinical application is limited due to its poor aqueous *** this study,we demonstrated that TA could inhibit epithelial-mesenchymal transition(EMT)and migration of A549 cells by inhibiting the transforming growth factor-β1(TGF-β1)/Smad signaling *** improve the aqueous solubility and pulmonary administration performance of TA,we prepared TA loaded methoxy poly(ethylene glycol)-poly(d,l-lactide)(mPEG-PLA)/d-α-tocopheryl polyethylene glycol succinate(TPGS)mixed polymeric mi-celles(TA-PM).Then a MicroSprayer^(R) Aerosolizer was used to deliver TA-PM once every two days for three weeks to evaluate their therapeutic effects on bleomycin(BLM)-induced IPF *** results demonstrated that inhaled TA-PM significantly inhibited BLM-induced inflammation,oxidative stress and fibrosis in lung ***,TA-PM exhibited high pulmonary deposition and retention by pul-monary administration,along with a favorable safety ***,this study emphasizes the potential of inhaled TA-PM as a promising treatment for IPF,providing a new opportunity for their clinical appli-cation.

关键词： Taraxasterol idiopathic pulmonary fibrosis Mixed polymeric micelles pulmonary administration Bleomycin

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Effects of Qizhukangxian granules on idiopathic pulmonary fibrosis:a randomized,double blind,placebo-controlled and multicenter clinical pilot trial

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Journal of Traditional Chinese Medicine 2020年第4期40卷 674-682页

作者： Guo Sijia Song Yalin Feng Jihong Liu Shuang Li Yuechuan Liu Min Wei Luqing Zhang Xian Xie Hui Sun Zengtao Department of Respiratory Medicine the Second Affiliated Hospital of Tianjin University of Traditional Chinese MedicineTianjin 300250China Department of Neurology the Second Affiliated Hospital of Tianjin University of Traditional Chinese MedicineTianjin 300250China Department of Hospital Management Tianjin University of Traditional Chinese MedicineTianjin 300193China Department of Respiratory Medicine Tianjin Chest HospitalTianjin 300300China Department of Respiratory Medicine the First Affiliated Hospital of Tianjin University of Traditional Chinese MedicineTianjin 300193China Department of Respiratory Medicine the Affiliated Hospital of Tianjin Armed Police Medical CollegeTianjin 300162China Department of Respiratory Medicine Tianjin Beichen Traditional Chinese Medicine HospitalTianjin 300400China Department of Respiratory Medicine Tianjin Dongli Traditional Chinese Medicine HospitalTianjin 300300China

OBJECTIVE:To evaluate the effects of Qizhukangxian granules(QG)on idiopathic pulmonary fibrosis(IPF).METHODS:This is a randomized,double blind,placebo-controlled and multicenter clinical pilot *** medical centers in Tianjin,China,participated in the study.A total of 120 IPF patients were enrolled and randomized into two groups,with 60 patients in each *** treatment group was treated with QG,while the control group received a Qizhukangxian *** pharmacological treatment lasted for 48 weeks from the enrollment *** indexes of patients were recorded on the admission day and at the end of the 24th and 48th *** were analyzed to study the effects of QG;forced vital capacity,change in forced vital capacity and maximal 6-min walk test(6MWT)distance were the primary *** endpoints were percentage of patients with episodes of acute exacerbation of IPF,pulmonary function,changes in pulse oxygen saturation during the 6MWT,dyspnea score,***'s respiratory questionnaire score,arterial blood gas analyses and the total Traditional Chinese Medicine symptom pattern ***:After 24 weeks of treatment,QG showed greater efficacy than the placebo in certain parameters,including the dyspnea score,Traditional Chinese Medicine symptom pattern score and some indicators in the ***'s respiratory questionnaire *** of the indexes obtained from all patients at the end of the 48th week showed that the therapeutic effects in the treatment group were significantly better than those in the control group because remarkable differences were observed in most of the primary and secondary endpoints between the two groups,except for the maximal distance of the 6MWT and arterial blood gas *** adverse reaction was observed in either group during the 48-week trial treatment ***:QG could effectively treat IPF patients by ameliorating pulmonary function,improving the quality of life and lowering the percentage of acu

关键词： idiopathic pulmonary fibrosis Vital capacity Walk test Randomized controlled trial Qizhukangxian granules

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Trigonelline mitigates bleomycin-induced idiopathic pulmonary fibrosis in mice

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Asian Pacific Journal of Tropical Biomedicine 2024年第9期14卷 391-400,I0008-I0291页

作者： Swapnil Gavhane Chandrakant Gawli Sachin Kumar Biswajit Das Gayatri Marathe Vishal S.Patil Harun M.Patel Basavaraj Bommanahalli Chanakya Nath Kundu Chandragouda R.Patil R.C.Patel Institute of Pharmaceutical Education and Research Karwand NakaShirpurMaharashtra 425405India Department of Pharmacology Delhi Pharmaceutical Sciences and Research UniversityNew Delhi 110017India School of Biotechnology Kalinga Institute of Industrial TechnologyBhubaneshwar 751024India Gadag Institute of Medical Sciences GadagKarnataka 582103India

Objective:To evaluate the effect of trigonelline on bleomycin-induced idiopathic pulmonary fibrosis(IPF)and to explore its underlying mechanisms using network ***:IPF was induced in C57BL/6 mice by a single intratracheal instillation of bleomycin(5 mg/kg).Trigonelline was administered at doses of 25,50,and 100 mg/kg/day orally from the 2nd day post-bleomycin induction up to the 14th *** IPF-induced mice,lung coefficient,immune cell infiltration in bronchoalveolar lavage fluid,and oxidative stress were *** alterations in lung tissues were also ***,network pharmacology approach was conducted to reveal molecular interactions of bleomycin and trigonelline with targets of ***:Trigonelline treatment reduced bleomycin-induced oxidative stress and immune cell infiltration,and mitigated physiological changes in the lung tissues of ***,trigonelline alleviated bleomycin-induced histological alterations in lung *** pharmacology analysis showed that bleomycin and trigonelline interacted with IPF targets,such as NFKB1,HDAC2,HIF1A,and ***:The interaction of trigonelline with key IPF targets and its ameliorative effects on lung damage and oxidative stress highlight its potential in treating *** may be considered an antifibrotic agent for further clinical development.

关键词： Trigonelline idiopathic pulmonary fibrosis Antifibrotic Bleomycin Network pharmacology

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