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BIBTEX RIS

Discovery of sulfonyl hydrazone derivative as a new selective PDE4A and PDE4D inhibitor by lead-optimization approach on the prototype LASSBio-448: In vitro and in vivo preclinical studies

2020; Elsevier BV; Volume: 204; Linguagem: Inglês

10.1016/j.ejmech.2020.112492

1768-3254

Isabelle Karine da Costa Nunes, Éverton Tenório de Souza, Italo Rossi Roseno Martins, Gisele Barbosa, Manoel Oliveira de Moraes, Millena de Melo Medeiros, Sheyla Welma Duarte Silva, Tatiane Luciano Balliano, Bagnólia Araújo da Silva, Patrı́cia Silva, Vinícius F. Carvalho, Marco A. Martins, Lı́dia Moreira Lima,

Phenothiazines and Benzothiazines Synthesis and Activities

Phosphodiesterase 4 (PDE4) inhibitors have emerged as a new strategy to treat asthma and other lung inflammatory diseases. Searching for new PDE4 inhibitors, we previously reported the discover of LASSBio-448, a sulfonamide with potential to prevent and reverse pivotal pathological features of asthma. In this paper, two novel series of sulfonamide (6a-6m) and sulfonyl hydrazone (7a-7j) analogues of LASSBio-448 have been synthetized and evaluated for selective inhibitory activity toward cAMP-specific PDE4 isoforms. From these studies, we have identified 7j (LASSBio-1632) as a new anti-asthmatic lead-candidate associated with selective inhibition of PDE4A and PDE4D isoenzymes and blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue. In addition, it was able to relax guinea pig trachea on non-sensitized and sensitized animals and showed great TGI permeability.