Pharmacologic and Pharmacodynamic Effects of the Selective Low Km Cyclic AMP Phosphodiesterase III Inhibitors WIN 63291 and WIN 62582

We describe the biochemical, pharmacologic, and in vivo pharmacodynamic profiles of two novel inhibitors of the cyclic GMP-inhibitable, low Km cyclic AMP phosphodiesterase (PDE) III; WIN 63291, a 6-qui-nolinyl analogue of the prototypic PDE III inhibitor milrinone and WIN 62582, an imidazopyridinone. Both WIN 62582 and WIN 63291 competitively inhibit PDE HI from rat, dog, and human heart and from rat and canine aorta with IC50 values of 5–37 and 55–80 nM, respectively; the IC50 values for milrinone ranged from 300 to 520 nM. WIN 62582 and WIN 63291 are at least 1,000-fold selective for PDE III relative to inhibition of PDE isozymes I, II, IV, and V. We evaluated WIN 62582 and WIN 63291 in conscious rats and dogs after intravenous (i.v.) and oral (p.o.) administration. The dose of WIN 62582 required to reduce mean arterial blood pressure (MAP) by 20% (ED20) in rats was 1.8 mg/kg, with a pharmacodynamic duration of action of ±2 h. In comparison, the estimated i.v. ED20 for WIN 63291 in rats was 0.4 mg/kg, with a pharmacodynamic duration of action >6 h. In conscious dogs, the i.v. doses of WIN 62582 and 63291 required to increase left ventricular (LV) dP/dtmax significantly were 0.1 and 0.01 mg/kg, respectively. In dogs, WIN 63291 0.1 mg/kg p.o. increased LVdP/dtmax by 86% in 30 min; LVdp/dtmax remained increased by 60% for at least 6 h. In comparison, WIN 62582, 0.3 mg/kg p.o., increased LVdP/dt by 56% in 30 min and remained increased by 40% at 6 h. These data suggest that WIN 62582 and WIN 63291 are potent, selective, orally active inhibitors of PDE III and have a relatively long duration of action in vivo. Although WIN 62582 is 10-fold more potent than WIN 63291 as an inhibitor of PDE III in vitro, WIN 63291 is a slightly more potent cardiovascular agent in vivo after i.v. and p.o. administration to conscious rats and dogs.