Substituted 4-(2,2-diphenylethyl)pyridine-N-oxides as phosphodiesterase-4 inhibitors: SAR study directed toward the improvement of pharmacokinetic parameters

Bioorg Med Chem Lett. 2002 Oct 21;12(20):3009-13. doi: 10.1016/s0960-894x(02)00615-7.

Abstract

A detailed SAR study directed toward the optimization of pharmacokinetic parameters for analogues of L-791,943 is reported. The introduction of a soft metabolic site on this structure permitted the identification of L-826,141 as a potent phosphodiesterase type 4 (PDE4) inhibitor that is well absorbed and that presents a shorter half-life than L-791,943 in a variety of animal species. The efficacy of L-826,141 is also demonstrated in different in vivo models.

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • Alkylation
  • Animals
  • Biological Availability
  • Cell Line
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Half-Life
  • Humans
  • Indicators and Reagents
  • Phosphodiesterase Inhibitors / chemical synthesis*
  • Phosphodiesterase Inhibitors / pharmacokinetics
  • Phosphodiesterase Inhibitors / pharmacology*
  • Pyridines / chemical synthesis
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology
  • Rats
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / chemical synthesis
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Indicators and Reagents
  • L-791943
  • Phosphodiesterase Inhibitors
  • Pyridines
  • Tumor Necrosis Factor-alpha
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 4