Structure-activity relationship studies on ortho-substituted cinnamic acids, a new class of selective EP(3) antagonists.
A series of novel ortho-substituted cinnamic acids have been synthesized, and their binding activity and selectivity on the four prostaglandin E(2) receptors evaluated. Many of them are very potent and selective EP(3) antagonists (K(i) 3-10 nM), while compound 9 is a very good and selective EP(2) agonist (K(i) 8 nM). The biological profile of the EP(2) agonist 9 in vivo and the metabolic profile of selected EP(3) antagonists are also reported.
Belley
Michel
M
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Québec, Canada H9R 4P8. belley@merck.com
Gallant
Michel
M
Roy
Bruno
B
Houde
Karine
K
Lachance
Nicolas
N
Labelle
Marc
M
Trimble
Laird A
LA
Chauret
Nathalie
N
Li
Chun
C
Sawyer
Nicole
N
Tremblay
Nathalie
N
Lamontagne
Sonia
S
Carrière
Marie-Claude
MC
Denis
Danielle
D
Greig
Gillian M
GM
Slipetz
Deborah
D
Metters
Kathleen M
KM
Gordon
Robert
R
Chan
Chi Chung
CC
Zamboni
Robert J
RJ
D002460:Cell Line; D002934:Cinnamates / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D010599:Pharmacokinetics; D011485:Protein Binding; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013329:Structure-Activity Relationship
D002934:Cinnamates; C545644:PTGER2 protein, human; C545647:PTGER3 protein, human; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D000242:Cyclic AMP