Biarylcarboxylic Acids and -Amides: Inhibition of Phosphodiesterase Type IV Versus [3H]rolipram Binding Activity and Their Relationship to Emetic Behavior in the Ferret

J Med Chem. 1996 Jan 5;39(1):120-5. doi: 10.1021/jm9505066.

Abstract

In addition to having desirable inhibitory effects on inflammation, anaphylaxis, and smooth muscle contraction, PDE-IV inhibitors also produce undesirable side effects including nausea and vomiting. In general, compounds that inhibit PDE-IV also potently displace [3H]rolipram from a high-affinity binding site in rat cortex. While this binding site has not been identified, it has been proposed to be an allosteric binding site on the PDE-IV enzyme. Preliminary studies have suggested that the emetic potency of PDE-IV inhibitors is correlated with affinity for the brain rolipram binding site rather than potency at inhibiting PDE-IV enzyme activity. Efforts to eliminate the emetic potential of PDE-IV inhibitors were directed toward developing compounds with decreased [3H]rolipram binding affinity while retaining PDE-IV potency. Thus, a novel series of 4-(3-alkoxy-4-methoxyphenyl)benzoic acids and their corresponding carboxamides were prepared and evaluated for their PDE-IV inhibitory and rolipram binding site properties. Modification of the catechol ether moiety led to phenylbutoxy and phenylpentoxy analogues that provided the desired activity profile. Specifically, 4-[3-(5-phenylpentoxy)-4-methoxyphenyl]-2-methylbenzoic acid, 18, was found to exhibit potent PDE-IV inhibitory activity (IC50 0.41 microM) and possessed 400 times weaker activity than rolipram for the [3H]rolipram binding site. In vivo, compound 18 was efficacious in the guinea pig aerosolized antigen induced airway obstruction assay (ED50 8.8 mg/kg, po) and demonstrated a significant reduction in emetic side effects (ferret, 20% emesis at 30 mg/kg, po).

Publication types

  • Comparative Study

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases*
  • Animals
  • Benzoates* / chemical synthesis
  • Benzoates* / chemistry
  • Benzoates* / metabolism
  • Benzoates* / pharmacology*
  • Binding Sites
  • Brain / drug effects
  • Brain / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Ferrets
  • Guinea Pigs
  • Humans
  • Mice
  • Phosphodiesterase Inhibitors / chemical synthesis
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / metabolism
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoric Diester Hydrolases / metabolism*
  • Pyrrolidinones / metabolism*
  • Rolipram
  • Structure-Activity Relationship
  • Vomiting / chemically induced

Substances

  • 4-(4-methoxy-3-(5-phenylpentoxy)phenyl)-2-methylbenzoic acid
  • Benzoates
  • Phosphodiesterase Inhibitors
  • Pyrrolidinones
  • Phosphoric Diester Hydrolases
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Rolipram