3-(2-Aminocarbonylphenyl)propanoic acid analogs as potent and selective EP3 receptor antagonists. part 2: optimization of the side chains to improve in vitro and in vivo potencies.
A series of 3-[2-{[(3-methyl-1-phenylbutyl)amino]carbonyl}-4-(phenoxymethyl)phenyl]propanoic acid analogs were synthesized and evaluated for their in vitro potency. In most cases, introduction of one or two substituents into the two phenyl moieties resulted in the tendency of an increase or retention of in vitro activities. Several compounds, which showed excellent subtype selectivity, were evaluated for their inhibitory effect against PGE(2)-induced uterine contraction in pregnant rats, which is thought to be mediated by the EP3 receptor subtype. The structure-activity relationships (SARs) are also discussed.
Asada
Masaki
M
Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan. m.asada@ono.co.jp
Iwahashi
Maki
M
Obitsu
Tetsuo
T
Kinoshita
Atsushi
A
Nakai
Yoshihiko
Y
Onoda
Takahiro
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; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011247:Pregnancy; D011422:Propionates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D014590:Uterine Contraction / Q000187:drug effects
D011422:Propionates; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype