3-(2-Aminocarbonylphenyl)propanoic acid analogs as potent and selective EP3 receptor antagonists. Part 1: discovery and exploration of the carboxyamide side chain.
A series of 3-(2-aminocarbonyl-4-phenoxymethylphenyl)propanoic acid analogs were synthesized and evaluated for their EP3 antagonist activity in the presence of additive serum albumin. Several compounds were biologically evaluated for their in vivo efficacy with respect to the PGE(2)-induced uterine contraction in pregnant rats as well as their pharmacokinetics. The discovery process of these potent and selective EP3 antagonists and their structure activity relationship are also presented.
Asada
Masaki
M
Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan. m.asada@ono.co.jp
Obitsu
Tetsuo
T
Nagase
Toshihiko
T
Tanaka
Motoyuki
M
Yamaura
Yoshiyuki
Y
Takizawa
Hiroya
H
Yoshikawa
Ken
K
Sato
Kazutoyo
K
Narita
Masami
M
Ohuchida
Shuichi
S
Nakai
Hisao
H
Toda
Masaaki
M
D000818:Animals; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D051379:Mice; D010647:Phenyl Ethers; D011247:Pregnancy; D011422:Propionates / Q000737:chemistry; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D012710:Serum Albumin, Bovine / Q000378:metabolism; D014590:Uterine Contraction / Q000187:drug effects*
C548852:3-(2-aminocarbonyl-4-phenoxymethylphenyl)propanoic acid; D010647:Phenyl Ethers; D011422:Propionates; C545648:Ptger3 protein, mouse; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D012710:Serum Albumin, Bovine