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-quinolinyl analogue of the prototypic PDE III inhibitor milrinone and WIN 62582, an imidazopyridinone. Both WIN 62582 and WIN 63291 competitively inhibit PDE III 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 approximately 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Pagani
E D
ED
Department of Vascular and Biochemical Pharmacology, Sterling Winthrop Pharmaceuticals Research Division, Collegeville, Pennsylvania 19426.
Dundore
R L
RL
Bode
D C
DC
Bacon
E R
ER
Singh
B
B
Lesher
G Y
GY
Buchholz
R A
RA
Silver
P J
PJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007275:Injections, Intravenous; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D020105:Milrinone / Q000031:analogs & derivatives; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D007093:Imidazoles; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D011728:Pyridones; D011804:Quinolines; C091174:WIN 62582; C091175:WIN 63291; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D020105:Milrinone