CARDIOVASCULAR ACTIVITY OF WIN-65579, A NOVEL INHIBITOR OF CYCLIC-GMPPHOSPHODIESTERASE-5

This study describes the phosphodiesterase inhibitory potency and card iovascular actions of WIN 65579 xy-4-pyrridyl)-1H-pyrazolo[3,4-d]pyrim idin-4-one), a potent, new cGMP phosphodiesterase 5 inhibitor. WIN 655 79 is a competitive inhibitor of phosphodiesterase 5, with IC50 values of 2-3 nM for phosphodiesterase 5 from human or canine vascular sourc es. WIN 65579 has low affinity for phosphodiesterases 1, 2 and 3 (IC50 > 3-10 mu M), and is somewhat selective for phosphodiesterase 4 (IC50 similar to 100 nM). WIN 65579 is an endothelial-dependent relaxant of rat aortic smooth muscle (EC50 = 60 nM) and lowers mean arterial bloo d pressure in conscious spontaneous hypertensive rats following intrav enous or oral dosing. WIN 65579 also increases plasma cGMP levels, and reinstates vascular responsiveness to nitroglycerin in conscious rats that are nitroglycerin-tolerant. These data show that WIN 65579 is on e of the more potent phosphodiesterase 5 inhibitors, and that WIN 6557 9 possesses cardiovascular activities consistent with vascular phospho diesterase 5 inhibition in vivo. (C) 1998 Elsevier Science B.V. All ri ghts reserved.