Non-peptide glycoprotein IIb/IIIa inhibitors. 17. Design and synthesis of orally active, long-acting non-peptide fibrinogen receptor antagonists.
The synthesis and pharmacological evaluation of 5 (L-738, 167), a potent, selective non-peptide fibrinogen receptor antagonist is reported. Compound 5 inhibited the aggregation of human gel-filtered platelets with an IC50 value of 8 nM and was found to be > 33000-fold less effective at inhibiting the attachment of human endothelial cells to fibrinogen, fibronectin, and vitronectin than it was at inhibiting platelet aggregation. Ex vivo platelet aggregation was inhibited by > 85% 24 h after the oral administration of 5 to dogs at 100 micrograms/kg. The extended pharmacodynamic profile exhibited by 5 appears to be a consequence of its high-affinity binding to GPIIb/IIIa on circulating platelets and suggests that 5 is suitable for once-a-day dosing.
Askew
B C
BC
Merck Research Laboratories, Department of Medicinal Chemistry, West point, Pennsylvania 19486, USA.
Bednar
R A
RA
Bednar
B
B
Claremon
D A
DA
Cook
J J
JJ
McIntyre
C J
CJ
Hunt
C A
CA
Gould
R J
RJ
Lynch
R J
RJ
Lynch
J J
JJ
Gaul
S L
SL
Stranieri
M T
MT
Sitko
G R
GR
Holahan
M A
MA
Glass
J D
JD
Hamill
T
T
Gorham
L M
LM
Prueksaritanont
T
T
Baldwin
J J
JJ
Hartman
G D
GD
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D019096:Vitronectin / Q000378:metabolism
D001381:Azepines; D005343:Fibrinolytic Agents; D005353:Fibronectins; C105929:L 738167; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013449:Sulfonamides; D019096:Vitronectin; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D003094:Collagen