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

Eur J Med Chem. 2020 Oct 15:204:112492. doi: 10.1016/j.ejmech.2020.112492. Epub 2020 Jul 18.

Abstract

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.

Keywords: Asthma; LASSBio-448; Lead-optimization; PDE4; Sulfonamide; Sulfonyl hydrazone.

MeSH terms

  • Animals
  • 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
  • Lung / drug effects
  • Lung / metabolism
  • Male
  • Mice

Substances

  • Enzyme Inhibitors
  • Hydrazones
  • Cyclic AMP
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4A protein, human
  • PDE4D protein, human