Discovery of 2-(phenoxypyridine)-3-phenylureas as small molecule P2Y1 antagonists.
Two distinct G protein-coupled purinergic receptors, P2Y1 and P2Y12, mediate ADP-driven platelet activation. The clinical effectiveness of P2Y12 blockade is well established. Recent preclinical data suggest that P2Y1 and P2Y12 inhibition provide equivalent antithrombotic efficacy, while targeting P2Y1 has the potential for reduced bleeding liability. In this account, the discovery of a 2-(phenoxypyridine)-3-phenylurea chemotype that inhibited ADP-mediated platelet aggregation in human blood samples is described. Optimization of this series led to the identification of compound 16, 1-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-4-(trifluoromethoxy)phenylurea, which demonstrated a 68 ± 7% thrombus weight reduction in an established rat arterial thrombosis model (10 mg/kg plus 10 mg/kg/h) while only prolonging cuticle and mesenteric bleeding times by 3.3- and 3.1-fold, respectively, in provoked rat bleeding time models. These results suggest that a P2Y1 antagonist could potentially provide a safe and efficacious antithrombotic profile.
Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton New Jersey 08543, United States. Hannguang.chao@bms.com
Hannguang
H
Chao
Huji
H
Turdi
Timothy F
TF
Herpin
Jacques Y
JY
Roberge
Yalei
Y
Liu
Dora M
DM
Schnur
Michael A
MA
Poss
Robert
R
Rehfuss
Ji
J
Hua
Qimin
Q
Wu
Laura A
LA
Price
Lynn M
LM
Abell
William A
WA
Schumacher
Jeffrey S
JS
Bostwick
Thomas E
TE
Steinbacher
Anne B
AB
Stewart
Martin L
ML
Ogletree
Christine S
CS
Huang
Ming
M
Chang
Angela M
AM
Cacace
Maredith J
MJ
Arcuri
Deborah
D
Celani
Ruth R
RR
Wexler
R Michael
RM
Lawrence
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000097:blood / Q000188:drug therapy; D001760:Bleeding Time; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D058921:Purinergic P2Y Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C582546:1-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-(4-(trifluoromethoxy)phenyl)urea; D005343:Fibrinolytic Agents; D010671:Phenylurea Compounds; D058921:Purinergic P2Y Receptor Antagonists; D011725:Pyridines; D014508:Urea