Antiplatelet and antiproliferative effects of SCH 51866, a novel type 1 and type 5 phosphodiesterase inhibitor.
SCH 51866 is a potent and selective PDE1 and PDE5 inhibitor. The antiplatelet, antiproliferative, and hemodynamic effects of SCH 51866 were compared with those of E4021, a highly selective PDE5 inhibitor. SCH 51866 inhibited PDE1 and PDE5 isozymes with a 50% inhibitory concentration (IC50) of 70 and 60 nM, respectively. SCH 51866 and E4021 inhibited washed human platelet aggregation induced by collagen with an IC50 of 10 and 4 microM, respectively, and attenuated (p < 0.05) the adhesion of 111indium-labeled platelets to the nylon filament-injured rat aorta. The doses of SCH 51866 and E4021 that inhibited platelet adhesion caused significant increases in platelet cyclic guanosine monophosphate (cGMP; p < 0.05). SCH 51866 (1-10 mg/kg, p.o. twice daily) but not E4021 (3-30 mg/kg, p.o twice daily) inhibited neointima formation in the carotid arteries of spontaneously hypertensive rats (SHRs) subjected to balloon angioplasty. Moreover, SCH 51866 (0.3-10 mg/kg, p.o.) elicited dose-dependent reduction in blood pressure in SHRs, whereas E4021 (3-30 mg/kg, p.o.) did not affect blood pressure in SHRs. In conclusion, the data suggest that inhibition of PDE1 and PDE5 isozymes by SCH 51866 exerts antiplatelet and vascular protective effects. In comparison, inhibition of PDE5 alone by E4021 exhibited antiplatelet effects without affecting neointima formation.
Vemulapalli
S
S
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Watkins
R W
RW
Chintala
M
M
Davis
H
H
Ahn
H S
HS
Fawzi
A
A
Tulshian
D
D
Chiu
P
P
Chatterjee
M
M
Lin
C C
CC
Sybertz
E J
EJ
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001158:Arteries / Q000166:cytology / Q000293:injuries / Q000503:physiopathology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D002455:Cell Division; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D007093:Imidazoles / Q000494:pharmacology*; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR
C091517:E 4021; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009712:Nucleotides, Cyclic; D010726:Phosphodiesterase Inhibitors; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D011799:Quinazolines; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; C517384:Pde5a protein, rat; C096501:SCH 51866