Synthesis, docking studies, pharmacological activity and toxicity of a novel pyrazole derivative (LQFM 021)--possible effects on phosphodiesterase

Chem Pharm Bull (Tokyo). 2013;61(5):524-31. doi: 10.1248/cpb.c12-01016.

Abstract

This study describes the synthetic route and molecular computational docking of LQFM 021, as well as examines its biological effects and toxicity. The docking studies revealed strong interaction of LQFM 021 to phosphodiesterase-3 (PDE-3). In isolated arteries, the presence of endothelium potentiates the relaxation for LQFM 021 and the inhibition cyclic nucleotides reduced the relaxation. Pre-contraction with KCl (45 mM), the treatment with tetraethylammonium (TEA) (5 mM) and inhibition of reticular Ca(2+)-ATPase showed an inhibitory effect on relaxation. Moreover, the compound reduced the contraction evoked by the Ca(2+) influx. Acute toxicity tests revealed that the compound was practically nontoxic. In conclusion, this study showed that a new synthetic derivative of pyrazole is a possible PDE-3 inhibitor and has vasorelaxant activity and low toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Cell Survival / drug effects
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Male
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Nucleotides, Cyclic / antagonists & inhibitors*
  • Nucleotides, Cyclic / metabolism
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Rats
  • Rats, Wistar
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / antagonists & inhibitors*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Structure-Activity Relationship
  • Tetrazoles / chemical synthesis
  • Tetrazoles / chemistry
  • Tetrazoles / pharmacology*

Substances

  • 5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)-2H-tetrazole
  • Enzyme Inhibitors
  • Nucleotides, Cyclic
  • Pyrazoles
  • Tetrazoles
  • pyrazole
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases