SELECTIVE TYPE-IV PHOSPHODIESTERASE INHIBITORS AS ANTIASTHMATIC AGENTS - THE SYNTHESES AND BIOLOGICAL-ACTIVITIES OF 3-(CYCLOPENTYLOXY)-4-METHOXYBENZAMIDES AND ANALOGS

The syntheses and biological activities of a number of benzamide deriv atives, designed from rolipram, which are selective inhibitors of cycl ic AMP-specific phosphodiesterase (PDE IV), are described. The effects of changes to the alkoxy groups, amide linkage, and benzamide N-pheny l ring on the inhibition of the cytosolic PDE IV from pig aorta have b een 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 obtain ed from and superoxide O-2(-) generation from guinea pig eosinophils i n vitro. Selected compounds have also been examined for their activiti es in inhibiting histamine-induced bronchospasm in anaesthetized guine a pigs. oxy)-N-(3,5-dichloro-4-pyridyl)-4-methoxybenzamide (15j) showe d exceptional potency in all tests and may have therapeutic potential in the treatment of asthma.