2,3-Diarylthiophenes as selective EP1 receptor antagonists.
The synthesis and the EP(1) receptor binding affinity of 2,3-diarylthiophene derivatives are described. The evaluation of the structure-activity relationship (SAR) in this series led to the identification of compounds 4, 7, and 12a, which exhibit high affinity for the human EP(1) receptor and a selectivity greater than 100-fold against the EP(2), EP(3), EP(4), DP, FP, and IP receptors and greater than 25-fold versus the TP receptor. These three antagonists present good pharmacokinetics in rats and significant differences in the way they are distributed in the brain.
Ducharme
Yves
Y
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Québec, Canada H9R 4P8. yves_ducgarme@merck.com
Blouin
Marc
M
Carrière
Marie-Claude
MC
Chateauneuf
Anne
A
Côté
Bernard
B
Denis
Danielle
D
Frenette
Richard
R
Greig
Gillian
G
Kargman
Stacia
S
Lamontagne
Sonia
S
Martins
Evelyn
E
Nantel
François
F
O'Neill
Gary
G
Sawyer
Nicole
N
Metters
Kathleen M
KM
Friesen
Richard W
RW
D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D006207:Half-Life; D006801:Humans; D010599:Pharmacokinetics; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D014018:Tissue Distribution
C545635:PTGER1 protein, human; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013876:Thiophenes