Species-dependent pharmacodynamic effects of the selective low Km cyclic AMP phosphodiesterase III inhibitors WIN 58993 and WIN 62005.
We describe the biochemical and pharmacologic effects of two novel fused pyridinones derived from milrinone: WIN 58993 and WIN 62005. Both WIN 58993 and WIN 62005 competitively inhibit cyclic GMP-inhibitable low Km cyclic AMP phosphodiesterase (PDE III) from rat heart and canine aorta with Ki values of 25 +/- 3 and 26 +/- 5 nM, respectively, and are selective (at least 160-fold) for PDE III inhibition relative to other PDE isozymes. WIN 58993 and WIN 62005 were given to conscious, chronically instrumented rats and dogs intravenously (i.v.) or perorally (p.o.). Because the doses of WIN 58993 and WIN 62005 required to decrease mean arterial blood pressure (MAP) by 20% were estimated to be 0.9 and 0.7 mg/kg, respectively, the compounds appear to be equipotent after acute i.v. administration in rats. However, the duration of the depressor responses in rats apparently differs since MAP remained significantly decreased 6 h after i.v. or p.o. administration of WIN 58993, but returned to control levels < or = 4 h after administration of WIN 62005. WIN 58993 may be slightly less potent than WIN 62005 after acute i.v. administration to dogs since significant increases in left ventricular (LV)dP/dtmax first occurred at doses of 0.1 and 0.03 mg/kg, respectively. LVdP/dtmax significantly increased in 30 min and returned to baseline 3 h after p.o. administration of 1 mg/kg WIN 58993. After p.o. administration of 1 mg/kg WIN 62005. LVdP/dtmax was significantly increased in 30 min and remained increased for at least 6 h. These data suggest that WIN 58993 and WIN 62005 are potent, selective, p.o.-active inhibitors of PDE III.(ABSTRACT TRUNCATED AT 250 WORDS)
Dundore
R L
RL
Department of Vascular and Biochemical Pharmacology, Sterling Winthrop Pharmaceuticals Research Division, Collegeville, Pennsylvania 19426-0900.
Pagani
E D
ED
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 / Q000201:enzymology; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006152:Cyclic GMP / Q000037:antagonists & inhibitors; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D007275:Injections, Intravenous; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
D002316:Cardiotonic Agents; D007093:Imidazoles; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D011728:Pyridones; D013844:Thiazoles; D014665:Vasodilator Agents; C093159:WIN 58993; C093158:WIN 62005; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D006152:Cyclic GMP; D020105:Milrinone