Synthesis and bioactivity of 3,5-dimethylpyrazole derivatives as potential PDE4 inhibitors

Bioorg Med Chem Lett. 2018 Oct 15;28(19):3276-3280. doi: 10.1016/j.bmcl.2018.03.031. Epub 2018 Mar 13.

Abstract

A series of 3,5-dimethylpyrazole derivatives containing 5-phenyl-2-furan moiety were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. Bioassay results showed that the title compounds exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNFα release. Among the designed compounds, compound If showed the best inhibitory activity against PDE4B with the IC50 value of 1.7 μM, which also showed good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary structure-activity relationship (SAR) study and docking results suggested that introduction of the substituent groups to the phenyl ring at the para-position, especially methoxy group, was helpful to enhance inhibitory activity against PDE4B.

Keywords: 3,5-Dimethylpyrazole derivatives; Molecular simulation; PDE4 inhibitor; SAR; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / drug therapy
  • Bronchoalveolar Lavage Fluid
  • Inhibitory Concentration 50
  • Mice
  • Phosphodiesterase 4 Inhibitors / chemical synthesis*
  • Phosphodiesterase 4 Inhibitors / pharmacology*
  • Phosphodiesterase 4 Inhibitors / therapeutic use
  • Pulmonary Disease, Chronic Obstructive / drug therapy
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / pharmacology*
  • Pyrazoles / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Sepsis / drug therapy
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Phosphodiesterase 4 Inhibitors
  • Pyrazoles
  • Tumor Necrosis Factor-alpha
  • 3,5-dimethylpyrazole