The discovery of 4-{1-[({2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]cyclopropyl}benzoic acid (MK-2894), a potent and selective prostaglandin E2 subtype 4 receptor antagonist.
The discovery of highly potent and selective second generation EP(4) antagonist MK-2894 (34d) is discussed. This compound exhibits favorable pharmacokinetic profile in a number of preclinical species and potent anti-inflammatory activity in several animal models of pain/inflammation. It also shows favorable GI tolerability profile in rats when compared to traditional NSAID indomethacin.
Blouin
Marc
M
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada Ltd., 16771 Trans-Canada Highway, Kirkland, QC, Canada. marc_blouin@merck.com
Han
Yongxin
Y
Burch
Jason
J
Farand
Julie
J
Mellon
Christophe
C
Gaudreault
Mireille
M
Wrona
Mark
M
Lévesque
Jean-François
JF
Denis
Danielle
D
Mathieu
Marie-Claude
MC
Stocco
Rino
R
Vigneault
Erika
E
Therien
Alex
A
Clark
Patsy
P
Rowland
Steve
S
Xu
Daigen
D
O'Neill
Gary
G
Ducharme
Yves
Y
Friesen
Rick
R
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010146:Pain / Q000188:drug therapy; D011448:Prostaglandin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics
D000700:Analgesics; D001565:Benzoates; D003521:Cyclopropanes; D011448:Prostaglandin Antagonists; D018078:Receptors, Prostaglandin E; D013876:Thiophenes