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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.
Eur J Pharmacol. 2019 Dec 15; 865:172779.EJ

Abstract

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.

Authors+Show Affiliations

Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland. Electronic address: katarzynaanna.wojcik@uj.edu.pl.Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, the Netherlands.Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.Department of Analytical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.Department of Analytical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, the Netherlands.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31705904

Citation

Wójcik-Pszczoła, Katarzyna, et al. "Novel Phosphodiesterases Inhibitors From the Group of Purine-2,6-dione Derivatives as Potent Modulators of Airway Smooth Muscle Cell Remodelling." European Journal of Pharmacology, vol. 865, 2019, p. 172779.
Wójcik-Pszczoła K, Chłoń-Rzepa G, Jankowska A, et al. Novel phosphodiesterases inhibitors from the group of purine-2,6-dione derivatives as potent modulators of airway smooth muscle cell remodelling. Eur J Pharmacol. 2019;865:172779.
Wójcik-Pszczoła, K., Chłoń-Rzepa, G., Jankowska, A., Ellen, E., Świerczek, A., Pociecha, K., Koczurkiewicz, P., Piska, K., Gawędzka, A., Wyska, E., Knapik-Czajka, M., Pękala, E., & Gosens, R. (2019). Novel phosphodiesterases inhibitors from the group of purine-2,6-dione derivatives as potent modulators of airway smooth muscle cell remodelling. European Journal of Pharmacology, 865, 172779. https://doi.org/10.1016/j.ejphar.2019.172779
Wójcik-Pszczoła K, et al. Novel Phosphodiesterases Inhibitors From the Group of Purine-2,6-dione Derivatives as Potent Modulators of Airway Smooth Muscle Cell Remodelling. Eur J Pharmacol. 2019 Dec 15;865:172779. PubMed PMID: 31705904.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel phosphodiesterases inhibitors from the group of purine-2,6-dione derivatives as potent modulators of airway smooth muscle cell remodelling. AU - Wójcik-Pszczoła,Katarzyna, AU - Chłoń-Rzepa,Grażyna, AU - Jankowska,Agnieszka, AU - Ellen,Eugenie, AU - Świerczek,Artur, AU - Pociecha,Krzysztof, AU - Koczurkiewicz,Paulina, AU - Piska,Kamil, AU - Gawędzka,Anna, AU - Wyska,Elżbieta, AU - Knapik-Czajka,Małgorzata, AU - Pękala,Elżbieta, AU - Gosens,Reinoud, Y1 - 2019/11/06/ PY - 2019/09/17/received PY - 2019/10/24/revised PY - 2019/11/04/accepted PY - 2019/11/11/pubmed PY - 2020/5/21/medline PY - 2019/11/10/entrez KW - ASMC hyperplasia KW - ASMC hypertrophy KW - Airway remodelling KW - Phosphodiesterases inhibitors KW - cAMP SP - 172779 EP - 172779 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 865 N2 - 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. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/31705904/Novel_phosphodiesterases_inhibitors_from_the_group_of_purine_26_dione_derivatives_as_potent_modulators_of_airway_smooth_muscle_cell_remodelling_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(19)30731-9 DB - PRIME DP - Unbound Medicine ER -