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Novel phosphodiesterases inhibitors from the group of purine-2,6-dione derivatives as potent modulators of airway smooth muscle cell remodelling

Wojcik-Pszczola, K., Chlon-Rzepa, G., Jankowska, A., Ellen, E., Swierczek, A., Pociecha, K., Koczurkiewicz, P., Piska, K., Gawedzka, A., Wyska, E., Knapik-Czajka, M., Pekala, E. & Gosens, R., 15-Dec-2019, In : European Journal of Pharmacology. 865, 11 p., 172779.

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  • Novel phosphodiesterases inhibitors from the group of purine-2,6-dionederivatives as potent modulators of airway smooth muscle cell remodelling

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DOI

  • Katarzyna Wojcik-Pszczola
  • Grazyna Chlon-Rzepa
  • Agnieszka Jankowska
  • Eugenie Ellen
  • Artur Swierczek
  • Krzysztof Pociecha
  • Paulina Koczurkiewicz
  • Kamil Piska
  • Anna Gawedzka
  • Elzbieta Wyska
  • Malgorzata Knapik-Czajka
  • Elzbieta Pekala
  • Reinoud Gosens

Airway remodelling (AR) is an important pathological feature of chronic asthma and chronic obstructive pulmonary disease. The etiology of AR is complex and involves both lung structural and immune cells. One of the main contributors to airway remodelling is the airway smooth muscle (ASM), which is thickened by asthma, becomes more contractile and produces more extracellular matrix. As a second messenger, adenosine 3',5'-cyclic monophosphate (cAMP) has been shown to contribute to ASM cell (ASMC) relaxation as well as to anti-remodelling effects in ASMC. Phosphodiesterase (PDE) inhibitors have drawn attention as an interesting new group of potential anti-inflammatory and anti-remodelling drugs. Recently, new hydrazide and amide purine-2,6-dione derivatives with anti-inflammatory properties have been synthesized by our team (compounds 1 and 2). We expanded our study of their PDE selectivity profile, ability to increase intracellular cAMP levels, metabolic stability and, above all, their capacity to modulate cell responses associated with ASMC remodelling. The results show that both compounds have subtype specificity for several PDE isoforms (including inhibition of PDE1, PDE3, PDE4 and PDE7). Interestingly, such combined PDE subtype inhibition exerts improved anti-remodelling efficacies against several ASMC-induced responses such as proliferation, contractility, extracellular matrix (ECM) protein expression and migration when compared to other non-selective and selective PDE inhibitors. Our findings open novel perspectives in the search for new chemical entities with dual anti-inflammatory and anti-remodelling profiles in the group of purine-2,6-dione derivatives as broad-spectrum PDE inhibitors.

Original languageEnglish
Article number172779
Number of pages11
JournalEuropean Journal of Pharmacology
Volume865
Publication statusPublished - 15-Dec-2019

    Keywords

  • Phosphod esterases inhibitors, cAMP, ASMC hypertrophy, ASMC hyperplasia, Airway remodelling, GROWTH-FACTOR-BETA, ASTHMA, PROLIFERATION, PATHOPHYSIOLOGY, HYPERTROPHY, ROFLUMILAST, CHALLENGES

ID: 112311238