Effects of New NSAID-CAI Hybrid Compounds in Inflammation and Lung Fibrosis
Laura Lucarini,
Mariaconcetta Durante,
Silvia Sgambellone,
Cecilia Lanzi,
Elisabetta Bigagli,
Ozlem Akgul,
Emanuela Masini,
Claudiu T. Supuran,
Fabrizio Carta
Affiliations
Laura Lucarini
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Viale G. Pieraccini n. 6, 50139 Florence, Italy
Mariaconcetta Durante
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Viale G. Pieraccini n. 6, 50139 Florence, Italy
Silvia Sgambellone
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Viale G. Pieraccini n. 6, 50139 Florence, Italy
Cecilia Lanzi
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Viale G. Pieraccini n. 6, 50139 Florence, Italy
Elisabetta Bigagli
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Viale G. Pieraccini n. 6, 50139 Florence, Italy
Ozlem Akgul
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ege University Bornova, 35100 Izmir, Turkey
Emanuela Masini
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Viale G. Pieraccini n. 6, 50139 Florence, Italy
Claudiu T. Supuran
Department of NEUROFARBA, Pharmaceutical Science Section, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy
Fabrizio Carta
Department of NEUROFARBA, Pharmaceutical Science Section, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy
Pulmonary fibrosis is a severe lung disease with progressive worsening of dyspnea, characterized by chronic inflammation and remodeling of lung parenchyma. Carbonic anhydrases are a family of zinc-metallo-enzymes that catalyze the reversible interconversion of carbon-dioxide and water to bicarbonate and protons. Carbonic Anhydrase Inhibitor (CAI) exhibited anti-inflammatory effects in animals with permanent-middle-cerebral artery occlusion, arthritis and neuropathic pain. The pharmacological profile of a new class of hybrid compounds constituted by a CAI connected to a Nonsteroidal-Anti-Inflammatory Drug (NSAID) was studied in the modulation of inflammation and fibrosis. In-vitro tests were performed to assess their effects on cyclo-oxygenase enzyme (COX)-1 and COX-2, namely inhibition of platelet aggregation and thromboxane B2 production in the human-platelet-rich plasma, and reduction of Prostaglandin-E2 production in lipopolysaccharide-treated-RAW-264.7 macrophage cell line. The activity of compound 3, one of the most active, was studied in a model of bleomycin-induced lung fibrosis in C57BL/6 mice. The hybrid compounds showed a higher potency in inhibiting PGE2 production, but not in modifying the platelet aggregation and the TXB2 production in comparison to the reference molecules, indicating an increased activity in COX-2 inhibition. In the in-vivo murine model, the compound 3 was more effective in decreasing inflammation, lung stiffness and oxidative stress in comparison to the reference drugs given alone or in association. In conclusion, these CAI-NSAID hybrid compounds are promising new anti-inflammatory drugs for the treatment of lung chronic inflammatory diseases.