1,4-Cyclohexanecarboxylates: potent and selective inhibitors of phosophodiesterase 4 for the treatment of asthma

J Med Chem. 1998 Mar 12;41(6):821-35. doi: 10.1021/jm970090r.

Abstract

Evaluation of a variety of PDE4 inhibitors in a series of cellular and in vivo assays suggested a strategy to improve the therapeutic index of PDE4 inhibitors by increasing their selectivity for the ability to inhibit PDE4 catalytic activity versus the ability to compete for high affinity [3H]rolipram-binding sites in the central nervous system. Use of this strategy led ultimately to the identification of cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxyl ic acid (1, SB 207499, Ariflo), a potent second-generation inhibitor of PDE4 with a decreased potential for side effects versus the archetypic first generation inhibitor, (R)-rolipram.

Publication types

  • Comparative Study

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • Animals
  • Anti-Asthmatic Agents / chemical synthesis
  • Anti-Asthmatic Agents / metabolism
  • Anti-Asthmatic Agents / pharmacology*
  • Anti-Asthmatic Agents / toxicity
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / metabolism
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Anti-Inflammatory Agents, Non-Steroidal / toxicity
  • Binding, Competitive
  • Body Temperature / drug effects
  • Brain / metabolism
  • Bronchoconstriction / drug effects
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Cyclohexanecarboxylic Acids / chemical synthesis
  • Cyclohexanecarboxylic Acids / metabolism
  • Cyclohexanecarboxylic Acids / pharmacology*
  • Cyclohexanecarboxylic Acids / toxicity
  • Dogs
  • Gastric Acid / metabolism
  • Guinea Pigs
  • Humans
  • Mice
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Nitriles
  • Phosphodiesterase Inhibitors / chemical synthesis
  • Phosphodiesterase Inhibitors / metabolism
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphodiesterase Inhibitors / toxicity
  • Pyrrolidinones / chemical synthesis
  • Pyrrolidinones / metabolism
  • Pyrrolidinones / pharmacology
  • Pyrrolidinones / toxicity
  • Rabbits
  • Recombinant Proteins / antagonists & inhibitors
  • Rolipram
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Vomiting / chemically induced

Substances

  • Anti-Asthmatic Agents
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclohexanecarboxylic Acids
  • Nitriles
  • Phosphodiesterase Inhibitors
  • Pyrrolidinones
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Cilomilast
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Rolipram