A novel series of potent and selective EP(4) receptor ligands: facile modulation of agonism and antagonism.
A novel series of EP(4) ligands, based on a benzyl indoline scaffold, has been discovered. It was found that agonism and antagonism in this series can be easily modulated by minor modifications on the benzyl group. The pharmacokinetic, metabolic and pharmacological profiles of these compounds was explored. It was found that these compounds show good pharmacokinetics in rat and are efficacious in pre-clinical models of pain and inflammation.
Department of Medicinal Chemistry, Merck Frosst Canada Inc., 16711 Trans-Canada Highway, Kirkland, Quebec, Canada. MICHAELJOHNBOYD@HOTMAIL.COM
Michael J
MJ
Boyd
Carl
C
Berthelette
Jean-François
JF
Chiasson
Patsy
P
Clark
John
J
Colucci
Danielle
D
Denis
Yongxin
Y
Han
Jean-Francois
JF
Lévesque
Marie-Claude
MC
Mathieu
Rino
R
Stocco
Alex
A
Therien
Steve
S
Rowland
Mark
M
Wrona
Daigen
D
Xu
D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008024:Ligands; D051381:Rats; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D007211:Indoles; D008024:Ligands; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; C057812:indoline