Selective type IV phosphodiesterase inhibitors as antiasthmatic agents. The syntheses and biological activities of 3-(cyclopentyloxy)-4-methoxybenzamides and analogues

J Med Chem. 1994 May 27;37(11):1696-703. doi: 10.1021/jm00037a021.


The syntheses and biological activities of a number of benzamide derivatives, designed from rolipram, which are selective inhibitors of cyclic AMP-specific phosphodiesterase (PDE IV), are described. The effects of changes to the alkoxy groups, amide linkage, and benzamide N-phenyl ring on the inhibition of the cytosolic PDE IV from pig aorta have been investigated. As a result, some highly potent and selective PDE IV inhibitors have been identified. The most potent compounds have been further evaluated for their inhibitory potencies against PDE IV obtained from and superoxide O2- generation from guinea pig eosinophils in vitro. Selected compounds have also been examined for their activities in inhibiting histamine-induced bronchospasm in anaesthetized guinea pigs. 3-(Cyclopentyloxy)-N-(3,5-dichloro-4-pyridyl)-4-methoxybenzamide (15j) showed exceptional potency in all tests and may have therapeutic potential in the treatment of asthma.

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • Animals
  • Aorta / enzymology
  • Asthma / drug therapy*
  • Benzamides / chemical synthesis*
  • Benzamides / pharmacology
  • Benzamides / therapeutic use
  • Bronchial Spasm / chemically induced
  • Bronchial Spasm / drug therapy
  • Eosinophils / drug effects
  • Eosinophils / metabolism
  • Guinea Pigs
  • Histamine / pharmacology
  • Isoenzymes / antagonists & inhibitors
  • Kinetics
  • Male
  • Molecular Structure
  • Phosphodiesterase Inhibitors / chemical synthesis*
  • Phosphodiesterase Inhibitors / pharmacology
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Structure-Activity Relationship
  • Superoxides / metabolism
  • Swine


  • Benzamides
  • Isoenzymes
  • Phosphodiesterase Inhibitors
  • Pyridines
  • Superoxides
  • Histamine
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • piclamilast