PHOSPHODIESTERASE-IV INHIBITION - RESPIRATORY MUSCLE-RELAXATION AND BRONCHODILATION BY WAY-PDA-641

The ability of 1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethanone (E)-O-(a minocarbonyl) oxime) (WAY-PDA-641) to inhibit cyclic AMP-metabolizing phosphodiesterases (PDEs) and to relax respiratory muscle was explored as part of a program to identify a PDE-IV inhibitor for potential use in the treatment of asthma. WAY-PDA-641 was identified as a preferent ial inhibitor of PDE-IV, possessing 36 times greater potency versus ca nine trachealis PDE-IV than PDE-III (IC50, 4.2 x 10(-7) M and 1.5 x 10 (-5) M, respectively). The classification of WAY-PDA-641 as a preferen tial PDE-IV inhibitor was supported in radioligand binding studies, wh ich demonstrated that 10 mu M WAY-PDA-641 did not displace ligands fro m a large number of receptors, and in functional studies, which used i solated guinea pig tracheal rings. Under conditions in which tracheal rings were made sensitive to the relaxant effects of PDE-IV or PDE-III inhibitors, WAY-PDA-641 induced relaxation with IC(50)s of 2.6 x 10(- 8) M (PDE-IV) and 3.2 x 10(-5) M (PDE-II;). Moreover, PDE-IV inhibitor y concentrations of WAY-PDA-641 significantly potentiated the relaxant effects of albuterol. WAY-PDA-641 reversed tracheal contractions indu ced by prostaglandin F-2 alpha, leukotriene Dq or histamine in a bipha sic manner consistent with its activity as a preferential PDE-IV inhib itor. The IC(50)s for reversal of each spasmogen were similar, which c onfirmed that WAY-PDA-641 is a functional antagonist of respiratory mu scle contraction. In an anesthetized beta-blocked serotonin-infused do g model, WAY-PDA-641 induced dose-dependent and virtually complete bro nchodilation (ED(50) = 0.01 mg/kg i.v.) with a biphasic dose-response relationship, without producing aminophylline-like cardiovascular chan ges. Thus, the results of these studies demonstrate that WAY-PDA-641 i s a preferential PDE-IV inhibitor with a pharmacological profile of po tential use in the treatment of asthma.