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

• Published in: European journal of medicinal chemistry 2020-10, Vol.204, p.112492-112492, Article 112492
• Main Authors: Nunes, Isabelle Karine da Costa, de Souza, Everton Tenório, Martins, Italo Rossi Roseno, Barbosa, Gisele, Moraes Junior, Manoel Oliveira de, Medeiros, Millena de Melo, Silva, Sheyla Welma Duarte, Balliano, Tatiane Luciano, da Silva, Bagnólia Araújo, Silva, Patrícia Machado Rodrigues, Carvalho, Vinicius de Frias, Martins, Marco Aurélio, Lima, Lidia Moreira
• Format: Article
• Language: English
• Subjects: Animals; Asthma; Cyclic AMP - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Drug Design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Humans; Hydrazones - chemistry; Hydrazones - pharmacology; Hydrazones - therapeutic use; Hypersensitivity - drug therapy; LASSBio-448; Lead-optimization; Lung - drug effects; Lung - metabolism; Male; Mice; PDE4; Sulfonamide; Sulfonyl hydrazone
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112492

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. [Display omitted] •A new selective PDE4A and PDE4D inhibitor.•Good drug-like properties.•Blockade of airway hyper-reactivity (AHR) and TNF-α production in the lung tissue.•relaxant effects on guinea pig trachea.