Characterization of ORG 20241, a combined phosphodiesterase IV/III cyclic nucleotide phosphodiesterase inhibitor for asthma.

The pharmacological profile of a novel cyclic nucleotide phosphodiesterase (PDE) inhibitor, Org 20241, has been characterized. The compound selectively inhibits PDE IV (pIC50, 5.2-6.1) and PDE III (pIC50, 4.4-4.6) from animal and human tissues. Org 20241 relaxed preparations of bovine trachea (pD2, 5.9 and 5.4), guinea pig trachea (pD2, 6.2 and 4.9) and human bronchi (pD2, 5.3 and 4.7) for histamine and methacholine-induced contractions, respectively. Rolipram and Org 20241 inhibited leukotriene B4-induced thromboxaneB2 (IC50, 0.3 and 1.4 microM, respectively) and H2O2 (IC50, 2.1 and 0.4 microM, respectively) production in guinea pig eosinophils. In phenylephrine (0.3 microM) precontracted rabbit aorta preparations, the PDE III inhibitor Org 9935 (pD2, 6.3 and 6.1 in the presence and absence of endothelium, respectively) was the most effective relaxant, whereas Org 20241 (pD2, 5.3 and 5.4 in the presence and absence of endothelium, respectively) was more effective than rolipram (pD2, 4.6 and 4.1 in the presence and absence of endothelium, respectively). Org 20241 relaxed rabbit aorta preparations and airway preparations at similar concentrations. In electrically stimulated rabbit cardiac papillary muscles, Org 20241 had little effect on contractility at concentrations up to 30 microM. Lower concentrations (10 microM) potentiated the inotropic effect of Org 9935. Whereas the PDE III inhibitor milrinone (1-100 microM) enhanced the rate of repolarization of guinea pig papillary muscles and shortened the effective refractory period, Org 20241 and rolipram (1-100 microM) did not reduce the action potential duration. In the presence of Org 20241 or rolipram, isoproterenol did not produce a greater increase in the rate of repolarization or reduction in the effective refractory period than in the absence of these PDE inhibitors. Org 20241 is a dual PDE IV/III inhibitor with some PDE IV selectively. This compound relaxes airways smooth muscle and inhibits eosinophil activation. The data indicate that such PDE IV/III inhibitors may be effective for the long-term therapy of asthma.