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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. Copyright © 2020 Elsevier Masson SAS. All rights reserved.


Isabelle Karine da Costa Nunes, Everton Tenório de Souza, Italo Rossi Roseno Martins, Gisele Barbosa, Manoel Oliveira de Moraes Junior, Millena de Melo Medeiros, Sheyla Welma Duarte Silva, Tatiane Luciano Balliano, Bagnólia Araújo da Silva, Patrícia Machado Rodrigues Silva, Vinicius de Frias Carvalho, Marco Aurélio Martins, Lidia Moreira Lima. 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. European journal of medicinal chemistry. 2020 Oct 15;204:112492

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PMID: 32717478

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