Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases , Anti-Allergic Agents/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Pyrazoles/pharmacology , Pyridines/pharmacology , Respiratory Hypersensitivity/drug therapy , Animals , Asthma/drug therapy , Bronchoconstriction/drug effects , Cyclic Nucleotide Phosphodiesterases, Type 4 , Eosinophils/drug effects , Guinea Pigs , Neutrophils/drug effects , Rats , Rats, Inbred BN , Trachea/drug effects , Trachea/enzymologyABSTRACT
The ability of 1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethanone (E)-O-(aminocarbonyl) 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 preferential inhibitor of PDE-IV, possessing 36 times greater potency versus canine 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 preferential PDE-IV inhibitor was supported in radioligand binding studies, which demonstrated that 10 microM WAY-PDA-641 did not displace ligands from a large number of receptors, and in functional studies, which used isolated 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 IC50S of 2.6 x 10(-8) M (PDE-IV) and 3.2 x 10(-5) M (PDE-III). Moreover, PDE-IV inhibitory concentrations of WAY-PDA-641 significantly potentiated the relaxant effects of albuterol. WAY-PDA-641 reversed tracheal contractions induced by prostaglandin F2 alpha, leukotriene D4 or histamine in a biphasic manner consistent with its activity as a preferential PDE-IV inhibitor. The IC50S for reversal of each spasmogen were similar, which confirmed that WAY-PDA-641 is a functional antagonist of respiratory muscle contraction.(ABSTRACT TRUNCATED AT 250 WORDS)