Purine-2,6-dione-based multitarget-directed ligands inhibiting PDE/TRPA1/CHIT1 as a new approach for the treatment of COPD.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent and frequently fatal respiratory disease. Current therapies for COPD do not fully target the pathogenic mechanisms of chronic inflammation, and therefore, the development of new, specific therapeutic strategies for the inflammatory process involved in the disease is urgently needed. In the present study, a focused series of novel 8-aminopurine-2,6-dione butanamides was synthesized, and their combined inhibitory activity against PDE/TRPA1/CHIT1 was evaluated. The most promising multifunctional ligands, 21, 39, and 47, exhibited anti-inflammatory and antifibrotic activities in human airway cell-based models, showing stronger effects than the reference compounds IBMX and HC-030031. Moreover, ligands 39 and 47 demonstrated more potent bronchodilatory effects ex vivo, surpassing theophylline and roflumilast. In vitro ADME-Tox data and pharmacokinetic results from in vivo studies confirmed the favorable drug-like properties of these compounds, including metabolic stability, absence of hepatotoxicity, satisfactory passive transport, and good lung penetration. Furthermore, compound 39 showed significant efficacy-comparable to that of roflumilast-after intraperitoneal (i.p.) administration in the elastase-induced emphysema murine model, which reflects key COPD symptoms and lung inflammation. This compound also reduced the level of the NLRP3 inflammasome multiprotein complex, thereby inhibiting its activation and reducing NF-κB phosphorylation. In summary, the data obtained in this study suggest that the innovative, multifunctional activity of compound 39 (as confirmed by molecular modeling studies predicting its binding mode) may represent a promising new strategy for the treatment of COPD.