Discovery and synthesis of a novel series of quinoline-based thrombin receptor (PAR-1) antagonists.
The design, synthesis, and SAR studies of a structurally novel series of highly potent thrombin receptor (PAR-1) antagonists are described. Compound 30 is a highly potent thrombin receptor antagonist (IC(50)=6.3 nM), a related compound 36 showing efficacy in a monkey ex vivo study.
Clasby
Martin C
MC
Central Nervous System and Cardiovascular Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. martin.clasby@spcorp.com
Chackalamannil
Samuel
S
Czarniecki
Michael
M
Doller
Dario
D
Eagen
Keith
K
Greenlee
William J
WJ
Lin
Yan
Y
Tsai
Hsingan
H
Xia
Yan
Y
Ahn
Ho-Sam
HS
Agans-Fantuzzi
Jacqueline
J
Boykow
George
G
Chintala
Madhu
M
Foster
Carolyn
C
Bryant
Matthew
M
Lau
Janice
J
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008252:Macaca fascicularis; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry*; D018179:Receptors, Thrombin / Q000378:metabolism; D013329:Structure-Activity Relationship
C505164:4-(5-(3-trifluoromethylphenyl)pyridin-2-yl)ethenyl-3-methyldecahydronaphtho(2,3-c)furan-1(3H)-one; D005343:Fibrinolytic Agents; D006575:Heterocyclic Compounds, 3-Ring; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D011804:Quinolines; D018179:Receptors, Thrombin; C037219:quinoline