Discovery and initial structure-activity relationships of trisubstituted ureas as thrombin receptor (PAR-1) antagonists.
Thrombin is the most potent agonist of platelet activation, and its effects are predominantly mediated by platelet thrombin receptors. Therefore, antagonists of the thrombin receptor have potential utility for the treatment of thrombotic disorders. Screening of combinatorial libraries revealed 2 to be a potent antagonist of the thrombin receptor. Modifications of this structure produced 11k, which inhibits thrombin receptor stimulated secretion and aggregation of platelets.
Barrow
J C
JC
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. james_barrow@merck.com
Nantermet
P G
PG
Selnick
H G
HG
Glass
K L
KL
Ngo
P L
PL
Young
M B
MB
Pellicore
J M
JM
Breslin
M J
MJ
Hutchinson
J H
JH
Freidinger
R M
RM
Condra
C
C
Karczewski
J
J
Bednar
R A
RA
Gaul
S L
SL
Stern
A
A
Gould
R
R
Connolly
T M
TM
D015539:Platelet Activation / Q000187:drug effects; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry / Q000494:pharmacology*
D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D014508:Urea