57000-13-2Relevant articles and documents
Novel phosphodiesterases inhibitors from the group of purine-2,6-dione derivatives as potent modulators of airway smooth muscle cell remodelling
?wierczek, Artur,Ch?oń-Rzepa, Gra?yna,Ellen, Eugenie,Gaw?dzka, Anna,Gosens, Reinoud,Jankowska, Agnieszka,Knapik-Czajka, Ma?gorzata,Koczurkiewicz, Paulina,P?kala, El?bieta,Piska, Kamil,Pociecha, Krzysztof,Wójcik-Pszczo?a, Katarzyna,Wyska, El?bieta
, (2019)
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.
Novel butanehydrazide derivatives of purine-2,6-dione as dual PDE4/7 inhibitors with potential anti-inflammatory activity: Design, synthesis and biological evaluation
Ch?oń-Rzepa, Gra?yna,Jankowska, Agnieszka,?lusarczyk, Marietta,?wierczek, Artur,Pociecha, Krzysztof,Wyska, El?bieta,Bucki, Adam,Gawalska, Alicja,Ko?aczkowski, Marcin,Paw?owski, Maciej
, p. 381 - 394 (2018/02/14)
A novel butanehydrazide derivatives of purine-2,6-dione designed using a ligand-based approach were synthesized and their in vitro activity against both PDE4B and PDE7A isoenzymes was assessed. The 7,8-disubstituted purine-2,6-dione derivatives 31, 34, 37, and 40 appeared to be the most potent PDE4/7 inhibitors with IC50 values in the range of that of the reference rolipram and BRL-50481, respectively. Moreover, docking studies explained the importance of N-(2,3,4-trihydroxybenzylidene)butanehydrazide substituent in position 7 of purine-2,6-dione core for dual PDE4/7 inhibitory properties. The inhibition of both the cAMP-specific PDE isoenzymes resulted in a strong anti-TNF-α effect. Compounds 31, 34, and 37 in the in vivo study in rats with LPS-induced endotoxemia decreased the maximum concentration of this proinflammatory cytokine by 53, 84 and 88%, respectively.
