Discovery of a nonpeptidic small molecule antagonist of the human platelet thrombin receptor (PAR-1).
The synthesis and biological evaluation of a series of nonpeptidic small molecule antagonists of the human platelet thrombin receptor (PAR-1) are described. Optimization of the 5-amino-3-arylisoxazole lead resulted in an approximate 100-fold increase in potency. The most potent of these compounds (54) inhibits platelet activation with IC(50)s of 90 nM against the thrombin receptor agonist peptide (TRAP) and 510 nM against thrombin as the agonist. Further, antagonist 54 fully blocks platelet aggregation stimulated by 1 nM thrombin for 10 min.
Nantermet
Philippe G
PG
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. phillipe_nantermet@merck.com
Barrow
James C
JC
Lundell
George F
GF
Pellicore
Janetta M
JM
Rittle
Kenneth E
KE
Young
MaryBeth
M
Freidinger
Roger M
RM
Connolly
Thomas M
TM
Condra
Cindra
C
Karczewski
Jerzy
J
Bednar
Rodney A
RA
Gaul
Stanley L
SL
Gould
Robert J
RJ
Prendergast
Kris
K
Selnick
Harold G
HG
D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors
C456400:5-(3-(hexahydroazepin-1-yl)propyl)(benzodioxol-5-yl)amino-3-(3,5-difluorophenyl)isoxazole; D001381:Azepines; D007202:Indicators and Reagents; D007555:Isoxazoles; D010446:Peptide Fragments; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; C072032:thrombin receptor peptide (42-55); D013917:Thrombin