CHARACTERIZATION OF ORG-20241, A COMBINED PHOSPHODIESTERASE IV III CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE INHIBITOR FOR ASTHMA/

The pharmacological profile of a novel cyclic nucleotide phosphodieste rase (PDE) inhibitor, Org 20241, has been characterized. The compound selectively inhibits PDE IV (plC(50), 5.2-6.1) and PDE III (plC(50), 4 .4-4.6) from animal and human tissues. Org 20241 relaxed preparations of bovine trachea (pD(2), 5.9 and 5.4), guinea pig trachea (pD(2), 6.2 and 4.9) and human bronchi (pD(2), 5.3 and 4.7) for histamine and met hacholine-induced contractions, respectively. Rolipram and Org 20241 i nhibited leukotriene B-4-induced thromboxaneB(2) (IC50 0.3 and 1.4 mu M, respectively) and H2O2 (IC50, 2.1 and 0.4 mu M, respectively) produ ction in guinea pig eosinophils. In phenylephrine (0.3 mu M) precontra cted rabbit aorta preparations, the PDE III inhibitor Org 9935 (pD(2), 6.3 and 6.1 in the presence and absence of endothelium, respectively) was the most effective relaxant, whereas Org 20241 (pD,, 5.3 and 5.4 in the presence and absence of endothelium, respectively) was more eff ective than rolipram (pD(2), 4.6 and 4.1 in the presence and absence o f endothelium, respectively). Org 20241 relaxed rabbit aorta preparati ons and airway preparations at similar concentrations. In electrically stimulated rabbit cardiac papillary muscles, Org 20241 had little eff ect on contractility at concentrations up to 30 mu M. Lower concentrat ions (10 mu M) potentiated the inotropic effect of Org 9935. Whereas t he PDE III inhibitor milrinone (1-100 mu M) enhanced the rate of repol arization of guinea pig papillary muscles and shortened the effective refractory period; Org 20241 and rolipram (1-100 mu M) did not reduce the action potential duration. In the presence of Org 20241 or rolipra m, isoproterenol did not produce a greater increase in the rate of rep olarization or reduction in the effective refractory period than in th e absence of these PDE inhibitors. Org 20241 is a dual PDE IV/III inhi bitor with some PDE IV selectivity. This compound relaxes airways smoo th muscle and inhibits eosinophil activation. The data indicate that s uch PDE IV/III inhibitors may be effective for the long-term therapy o f asthma.