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Pyrtriazoles, a Novel Class of Store-Operated Calcium Entry Modulators: Discovery, Biological Profiling, and in Vivo Proof-of-Concept Efficacy in Acute Pancreatitis
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    Article

    Pyrtriazoles, a Novel Class of Store-Operated Calcium Entry Modulators: Discovery, Biological Profiling, and in Vivo Proof-of-Concept Efficacy in Acute Pancreatitis
    Click to copy article linkArticle link copied!

    • Beatrice Riva
      Beatrice Riva
      Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara 28100, Italy
      ChemICare Srl, Enne3, Novara 28100, Italy
    • Alessia Griglio
      Alessia Griglio
      Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara 28100, Italy
    • Marta Serafini
      Marta Serafini
      Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara 28100, Italy
    • Celia Cordero-Sanchez
      Celia Cordero-Sanchez
      Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara 28100, Italy
    • Silvio Aprile
      Silvio Aprile
      Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara 28100, Italy
    • Rosanna Di Paola
      Rosanna Di Paola
      Department of Chemical, Biological, Pharmaceutical, and Enviromental Sciences, Università di Messina, Messina 98166, Italy
    • Enrico Gugliandolo
      Enrico Gugliandolo
      Department of Chemical, Biological, Pharmaceutical, and Enviromental Sciences, Università di Messina, Messina 98166, Italy
    • Dalia Alansary
      Dalia Alansary
      Department of Molecular Biophysics, Saarland University CIPMM, Homburg 66421, Germany
    • Isabella Biocotino
      Isabella Biocotino
      Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara 28100, Italy
    • Dmitry Lim
      Dmitry Lim
      Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara 28100, Italy
      More by Dmitry Lim
    • Giorgio Grosa
      Giorgio Grosa
      Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara 28100, Italy
    • Ubaldina Galli
      Ubaldina Galli
      Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara 28100, Italy
    • Barbara Niemeyer
      Barbara Niemeyer
      Department of Molecular Biophysics, Saarland University CIPMM, Homburg 66421, Germany
    • Giovanni Sorba
      Giovanni Sorba
      Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara 28100, Italy
    • Pier Luigi Canonico
      Pier Luigi Canonico
      Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara 28100, Italy
    • Salvatore Cuzzocrea
      Salvatore Cuzzocrea
      Department of Chemical, Biological, Pharmaceutical, and Enviromental Sciences, Università di Messina, Messina 98166, Italy
    • Armando A. Genazzani
      Armando A. Genazzani
      Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara 28100, Italy
    • Tracey Pirali*
      Tracey Pirali
      Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara 28100, Italy
      ChemICare Srl, Enne3, Novara 28100, Italy
      *Phone: 0039-0321-375852. Fax: 0039-0321-375821. E-mail: [email protected]. Address: Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy.
    Other Access OptionsSupporting Information (2)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2018, 61, 21, 9756–9783
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.8b01512
    Published October 22, 2018
    Copyright © 2018 American Chemical Society

    Abstract

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    In recent years, channels that mediate store-operated calcium entry (SOCE, i.e., the ability of cells to sense a decrease in endoplasmic reticulum luminal calcium and induce calcium entry across the plasma membrane) have been associated with a number of disorders, spanning from immune disorders to acute pancreatitis and have been suggested to be druggable targets. In the present contribution, we exploited the click chemistry approach to synthesize a class of SOCE modulators where the arylamide substructure that characterizes most inhibitors so far described is substituted by a 1,4-disubstituted 1,2,3-triazole ring. Within this series, inhibitors of SOCE were identified and the best compound proved effective in an animal model of acute pancreatitis, a disease characterized by a hyperactivation of SOCE. Strikingly, two enhancers of the process were discovered, affording invaluable research tools to further explore the (patho)physiological role of capacitative calcium entry.

    Copyright © 2018 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.8b01512.

    • Synthesis and characterization of alkyne J, azide K, compound 18, alkynes 52, 53, 54, 56, and 57; NMR spectra of 1S, 2T, 3G, 31, and 39; biology (effect of 2T on the area under the curve, the peak amplitude, and the slope of the Ca2+-rise in wild-type and shTRPC1 Hek cells; concentration–response curves in Hek, Jurkat, and BV2; list of primers; metabolic stability data for Pyr3, 1S, 30, 31, 39, and 43; chromatographic methods. (PDF)

    • Molecular formula strings (CSV)

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    Click to copy section linkSection link copied!

    This article is cited by 24 publications.

    1. Silvio Aprile, Beatrice Riva, Irene Preet Bhela, Celia Cordero-Sanchez, Giulia Avino, Armando A. Genazzani, Marta Serafini, Tracey Pirali. 1,2,4-Oxadiazole-Bearing Pyrazoles as Metabolically Stable Modulators of Store-Operated Calcium Entry. ACS Medicinal Chemistry Letters 2021, 12 (4) , 640-646. https://doi.org/10.1021/acsmedchemlett.1c00034
    2. Pavel K. Mykhailiuk. Fluorinated Pyrazoles: From Synthesis to Applications. Chemical Reviews 2021, 121 (3) , 1670-1715. https://doi.org/10.1021/acs.chemrev.0c01015
    3. Marta Serafini, Celia Cordero-Sanchez, Rosanna Di Paola, Irene P. Bhela, Silvio Aprile, Beatrice Purghè, Roberta Fusco, Salvatore Cuzzocrea, Armando A. Genazzani, Beatrice Riva, Tracey Pirali. Store-Operated Calcium Entry as a Therapeutic Target in Acute Pancreatitis: Discovery and Development of Drug-Like SOCE Inhibitors. Journal of Medicinal Chemistry 2020, 63 (23) , 14761-14779. https://doi.org/10.1021/acs.jmedchem.0c01305
    4. Iman Azimi, Ralph J. Stevenson, Xuexin Zhang, Aldo Meizoso-Huesca, Ping Xin, Martin Johnson, Jack U. Flanagan, Silke B. Chalmers, Ryan E. Yoast, Jeevak S. Kapure, Benjamin P. Ross, Irina Vetter, Mark R. Ashton, Bradley S. Launikonis, William A. Denny, Mohamed Trebak, Gregory R. Monteith. A New Selective Pharmacological Enhancer of the Orai1 Ca2+ Channel Reveals Roles for Orai1 in Smooth and Skeletal Muscle Functions. ACS Pharmacology & Translational Science 2020, 3 (1) , 135-147. https://doi.org/10.1021/acsptsci.9b00081
    5. Roberto Silva-Rojas, Laura Pérez-Guàrdia, Alix Simon, Sarah Djeddi, Susan Treves, Agnès Ribes, Lorenzo Silva-Hernández, Céline Tard, Jocelyn Laporte, Johann Böhm. ORAI1 inhibition as an efficient preclinical therapy for tubular aggregate myopathy and Stormorken syndrome. JCI Insight 2024, 9 (6) https://doi.org/10.1172/jci.insight.174866
    6. Frederick A. Luzzio. Diversity of heterocyclic reactants in the click reaction. 2024, 95-176. https://doi.org/10.1016/bs.aihch.2023.11.002
    7. Xiangjin Kong, Feifan Wang, Yan Chen, Xinyao Liang, Yuan Yin, Hao Liu, Guoqing Luo, Yinping Li, Songping Liang, Youjun Wang, Zhonghua Liu, Cheng Tang. Molecular action mechanisms of two novel and selective calcium release-activated calcium channel antagonists. International Journal of Biological Macromolecules 2023, 253 , 126937. https://doi.org/10.1016/j.ijbiomac.2023.126937
    8. Hussein N. Rubaiy. ORAI Calcium Channels: Regulation, Function, Pharmacology, and Therapeutic Targets. Pharmaceuticals 2023, 16 (2) , 162. https://doi.org/10.3390/ph16020162
    9. Feliciano Protasi, Barbara Girolami, Sara Roccabianca, Daniela Rossi. Store-operated calcium entry: From physiology to tubular aggregate myopathy. Current Opinion in Pharmacology 2023, 68 , 102347. https://doi.org/10.1016/j.coph.2022.102347
    10. Linjun Wu, Jing Hu, Xiaolin Yi, Jianqin Lv, Jiaqi Yao, Wenfu Tang, Shu Zhang, Meihua Wan. Gut microbiota interacts with inflammatory responses in acute pancreatitis. Therapeutic Advances in Gastroenterology 2023, 16 https://doi.org/10.1177/17562848231202133
    11. Celia Cordero-Sanchez, Emanuela Pessolano, Beatrice Riva, Mauro Vismara, Silvia Maria Grazia Trivigno, Nausicaa Clemente, Silvio Aprile, Federico Alessandro Ruffinatti, Paola Portararo, Nicoletta Filigheddu, Ivan Zaggia, Irene P. Bhela, Marta Serafini, Tracey Pirali, Mario P. Colombo, Mauro Torti, Sabina Sangaletti, Alessandra Bertoni, Armando A. Genazzani. CIC-39Na reverses the thrombocytopenia that characterizes tubular aggregate myopathy. Blood Advances 2022, 6 (15) , 4471-4484. https://doi.org/10.1182/bloodadvances.2021006378
    12. Yulia V. Krivolapova, Olesya A. Tomashenko, Liya D. Funt, Dar'ya V. Spiridonova, Mikhail S. Novikov, Alexander F. Khlebnikov. Azirine-triazole hybrids: selective synthesis of 5-(2 H -azirin-2-yl)-, 5-(1 H -pyrrol-2-yl)-1 H -1,2,3-triazoles and 2-(5-(2 H -azirin-2-yl)-1 H -1,2,3-triazol-1-yl)pyridines. Organic & Biomolecular Chemistry 2022, 20 (27) , 5434-5443. https://doi.org/10.1039/D2OB00908K
    13. Beatrice Riva, Emanuela Pessolano, Edoardo Quaglia, Celia Cordero-Sanchez, Irene P. Bhela, Ana Topf, Marta Serafini, Daniel Cox, Elizabeth Harris, Matteo Garibaldi, Rita Barresi, Tracey Pirali, Armando A. Genazzani. STIM1 and ORAI1 mutations leading to tubular aggregate myopathies are sensitive to the Store-operated Ca2+-entry modulators CIC-37 and CIC-39. Cell Calcium 2022, 105 , 102605. https://doi.org/10.1016/j.ceca.2022.102605
    14. Guilherme H. Souza Bomfim, Barbara A. Niemeyer, Rodrigo S. Lacruz, Annette Lis. On the Connections between TRPM Channels and SOCE. Cells 2022, 11 (7) , 1190. https://doi.org/10.3390/cells11071190
    15. Divya Adiga, Raghu Radhakrishnan, Sanjiban Chakrabarty, Prashant Kumar, Shama Prasada Kabekkodu. The Role of Calcium Signaling in Regulation of Epithelial-Mesenchymal Transition. Cells Tissues Organs 2022, 211 (2) , 134-156. https://doi.org/10.1159/000512277
    16. Elena Conte, Paola Imbrici, Paola Mantuano, Maria Antonietta Coppola, Giulia Maria Camerino, Annamaria De Luca, Antonella Liantonio. Alteration of STIM1/Orai1-Mediated SOCE in Skeletal Muscle: Impact in Genetic Muscle Diseases and Beyond. Cells 2021, 10 (10) , 2722. https://doi.org/10.3390/cells10102722
    17. Dmitry Lim, Giulia Dematteis, Laura Tapella, Armando A. Genazzani, Tito Calì, Marisa Brini, Alexei Verkhratsky. Ca2+ handling at the mitochondria-ER contact sites in neurodegeneration. Cell Calcium 2021, 98 , 102453. https://doi.org/10.1016/j.ceca.2021.102453
    18. Elena Lilliu, Stéphane Koenig, Xaver Koenig, Maud Frieden. Store-Operated Calcium Entry in Skeletal Muscle: What Makes It Different?. Cells 2021, 10 (9) , 2356. https://doi.org/10.3390/cells10092356
    19. Heba Shawer, Katherine Norman, Chew W. Cheng, Richard Foster, David J. Beech, Marc A. Bailey. ORAI1 Ca2+ Channel as a Therapeutic Target in Pathological Vascular Remodelling. Frontiers in Cell and Developmental Biology 2021, 9 https://doi.org/10.3389/fcell.2021.653812
    20. Elena Conte, Alessandra Pannunzio, Paola Imbrici, Giulia Maria Camerino, Lorenzo Maggi, Marina Mora, Sara Gibertini, Ornella Cappellari, Annamaria De Luca, Mauro Coluccia, Antonella Liantonio. Gain-of-Function STIM1 L96V Mutation Causes Myogenesis Alteration in Muscle Cells From a Patient Affected by Tubular Aggregate Myopathy. Frontiers in Cell and Developmental Biology 2021, 9 https://doi.org/10.3389/fcell.2021.635063
    21. Marta Serafini, Tracey Pirali, Gian Cesare Tron. Click 1,2,3-triazoles in drug discovery and development: From the flask to the clinic?. 2021, 101-148. https://doi.org/10.1016/bs.aihch.2020.10.001
    22. Achille Schild, Rajesh Bhardwaj, Nicolas Wenger, Dominic Tscherrig, Palanivel Kandasamy, Jan Dernič, Roland Baur, Christine Peinelt, Matthias A. Hediger, Martin Lochner. Synthesis and Pharmacological Characterization of 2-Aminoethyl Diphenylborinate (2-APB) Derivatives for Inhibition of Store-Operated Calcium Entry (SOCE) in MDA-MB-231 Breast Cancer Cells. International Journal of Molecular Sciences 2020, 21 (16) , 5604. https://doi.org/10.3390/ijms21165604
    23. Jingpei Huo, Chong Lin, Jinming Liang. A brief minireview of poly-triazole: Alkyne and azide substrate selective, metal-catalyst expansion. Reactive and Functional Polymers 2020, 152 , 104531. https://doi.org/10.1016/j.reactfunctpolym.2020.104531
    24. Marta Serafini, Enza Torre, Silvio Aprile, Alberto Massarotti, Silvia Fallarini, Tracey Pirali. Synthesis, Docking and Biological Evaluation of a Novel Class of Imidazothiazoles as IDO1 Inhibitors. Molecules 2019, 24 (10) , 1874. https://doi.org/10.3390/molecules24101874

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2018, 61, 21, 9756–9783
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.8b01512
    Published October 22, 2018
    Copyright © 2018 American Chemical Society

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