Discovery of novel pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione (PBD) derivatives as selective HDAC6 inhibitors for the efficient treatment of idiopathic pulmonary fibrosis (IPF) in vitro and in vivo

被引:3
作者
Li, Yanchun [1 ]
Yang, Huali [2 ]
Zhao, Xiangling [1 ]
Zhao, Xianchen [1 ]
Quan, Jishun [2 ]
Wang, Lei [2 ]
Ma, Enlong [1 ]
Ma, Chao [2 ]
机构
[1] Shenyang Pharmaceut Univ, Sch Life Sci & Biopharmaceut Sci, Dept Pharmacol, 103 Wenhua Rd, Shenyang 110016, Peoples R China
[2] Shenyang Pharmaceut Univ, Sch Pharmaceut Engn, Key Lab Struct Based Drug Design & Discovery, Minist Educ, 103 Wenhua Rd, Shenyang 110016, Peoples R China
关键词
Idiopathic pulmonary fibrosis (IPF); HDAC6; Selectivity; Pharmacological mechanism; Mouse model; DESIGN;
D O I
10.1016/j.ejmech.2024.116608
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by a progressive fibrotic phenotype. Immunohistochemical studies on HDAC6 overexpression in IPF lung tissues confirmed that IPF is associated with aberrant HDAC6 activity. We herein developed a series of novel HDAC6 inhibitors that can be used as potential pharmacological tools for IPF treatment. The best-performing derivative H10 showed good selectivity for multiple isoforms of the HDAC family. The structural analysis and structure-activity relationship studies of H10 will contribute to optimizing the binding mode of the new molecules. The pharmacological mechanism of H10 to inhibit pulmonary fibrosis was validated, and its ability to inhibit the IPF phenotype was also demonstrated. Moreover, H10 showed satisfactory metabolic stability. The efficacy of H10 was also determined in a mouse model of bleomycin-induced pulmonary fibrosis. The results highlighted in this paper may provide a reference for the identification of new drug molecules for the treatment of IPF.
引用
收藏
页数:16
相关论文
共 27 条
[1]  
Amy L.O., 2018, Eur. Respir. Rev., V27
[2]   Old but Gold: Tracking the New Guise of Histone Deacetylase 6 (HDAC6) Enzyme as a Biomarker and Therapeutic Target in Rare Diseases [J].
Brindisi, Margherita ;
Saraswati, A. Prasanth ;
Brogi, Simone ;
Gemma, Sandra ;
Butini, Stefania ;
Campiani, Giuseppe .
JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (01) :23-39
[3]   Rational Design and Simple Chemistry Yield a Superior, Neuroprotective HDAC6 Inhibitor, Tubastatin A [J].
Butler, Kyle V. ;
Kalin, Jay ;
Brochier, Camille ;
Vistoli, Guilio ;
Langley, Brett ;
Kozikowski, Alan P. .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2010, 132 (31) :10842-10846
[4]   Harnessing the Role of HDAC6 in Idiopathic Pulmonary Fibrosis: Design, Synthesis, Structural Analysis, and Biological Evaluation of Potent Inhibitors [J].
Campiani, Giuseppe ;
Cavella, Caterina ;
Osko, Jeremy D. ;
Brindisi, Margherita ;
Relitti, Nicola ;
Brogi, Simone ;
Saraswati, A. Prasanth ;
Federico, Stefano ;
Chemi, Giulia ;
Maramai, Samuele ;
Carullo, Gabriele ;
Jaeger, Benedikt ;
Carleo, Alfonso ;
Benedetti, Rosaria ;
Sarno, Federica ;
Lamponi, Stefania ;
Rottoli, Paola ;
Bargagli, Elena ;
Bertucci, Carlo ;
Tedesco, Daniele ;
Herp, Daniel ;
Senger, Johanna ;
Ruberti, Giovina ;
Saccoccia, Fulvio ;
Saponara, Simona ;
Gorelli, Beatrice ;
Valoti, Massimo ;
Kennedy, Breandan ;
Sundaramurthi, Husvinee ;
Butini, Stefania ;
Jung, Manfred ;
Roach, Katy M. ;
Altucci, Lucia ;
Bradding, Peter ;
Christianson, David W. ;
Gemma, Sandra ;
Prasse, Antje .
JOURNAL OF MEDICINAL CHEMISTRY, 2021, 64 (14) :9960-9988
[5]   Emerging therapeutic interventions for idiopathic pulmonary fibrosis [J].
Chakraborty, Sushmita ;
Chopra, Puneet ;
Ambi, Senthil V. ;
Dastidar, Sunanda G. ;
Ray, Abhijit .
EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2014, 23 (07) :893-910
[6]   Multiple roles of HDAC inhibition in neurodegenerative conditions [J].
Chuang, De-Maw ;
Leng, Yan ;
Marinova, Zoya ;
Kim, Hyeon-Ju ;
Chiu, Chi-Tso .
TRENDS IN NEUROSCIENCES, 2009, 32 (11) :591-601
[7]   Melatonin- and Ferulic Acid-Based HDAC6 Selective Inhibitors Exhibit Pronounced Immunomodulatory Effects In Vitro and Neuroprotective Effects in a Pharmacological Alzheimer's Disease Mouse Model [J].
He, Feng ;
Chou, C. James ;
Scheiner, Matthias ;
Poeta, Eleonora ;
Chen, Natalia Yuan ;
Gunesch, Sandra ;
Hoffmann, Matthias ;
Sotriffer, Christoph ;
Monti, Barbara ;
Maurice, Tangui ;
Decker, Michael .
JOURNAL OF MEDICINAL CHEMISTRY, 2021, 64 (07) :3794-3812
[8]   A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis [J].
King, Talmadge E., Jr. ;
Bradford, Williamson Z. ;
Castro-Bernardini, Socorro ;
Fagan, Elizabeth A. ;
Glaspole, Ian ;
Glassberg, Marilyn K. ;
Gorina, Eduard ;
Hopkins, Peter M. ;
Kardatzke, David ;
Lancaster, Lisa ;
Lederer, David J. ;
Nathan, Steven D. ;
Pereira, Carlos A. ;
Sahn, Steven A. ;
Sussman, Robert ;
Swigris, Jeffrey J. ;
Noble, Paul W. .
NEW ENGLAND JOURNAL OF MEDICINE, 2014, 370 (22) :2083-2092
[9]   iPSC-derived neurons profiling reveals GABAergic circuit disruption and acetylated α-tubulin defect which improves after iHDAC6 treatment in Rett syndrome [J].
Landucci, Elisa ;
Brindisi, Margherita ;
Bianciardi, Laura ;
Catania, Lorenza M. ;
Daga, Sergio ;
Croci, Susanna ;
Frullanti, Elisa ;
Fallerini, Chiara ;
Butini, Stefania ;
Brogi, Simone ;
Furini, Simone ;
Melani, Riccardo ;
Molinaro, Angelo ;
Lorenzetti, Flaminia Clelia ;
Imperatore, Valentina ;
Amabile, Sonia ;
Mariani, Jessica ;
Mari, Francesca ;
Ariani, Francesca ;
Pizzorusso, Tommaso ;
Pinto, Anna Maria ;
Vaccarino, Flora M. ;
Renieri, Alessandra ;
Campiani, Giuseppe ;
Meloni, Ilaria .
EXPERIMENTAL CELL RESEARCH, 2018, 368 (02) :225-235
[10]   (N-Hydroxycarbonylbenylamino)quinolines as Selective Histone Deacetylase 6 Inhibitors Suppress Growth of Multiple Myeloma in Vitro and in Vivo [J].
Lee, Hsueh-Yun ;
Nepali, Kunal ;
Huang, Fang-I ;
Chang, Chih-Yi ;
Lai, Mei-Jung ;
Li, Yu-Hsuan ;
Huang, Hsiang-Ling ;
Yang, Chia-Ron ;
Liou, Jing-Ping .
JOURNAL OF MEDICINAL CHEMISTRY, 2018, 61 (03) :905-917