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.
Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan. m.asada@ono.co.jp
Masaki
M
Asada
Maki
M
Iwahashi
Tetsuo
T
Obitsu
Atsushi
A
Kinoshita
Yoshihiko
Y
Nakai
Takahiro
T
Onoda
Toshihiko
T
Nagase
Motoyuki
M
Tanaka
Yoshiyuki
Y
Yamaura
Hiroya
H
Takizawa
Ken
K
Yoshikawa
Kazutoyo
K
Sato
Masami
M
Narita
Shuichi
S
Ohuchida
Hisao
H
Nakai
Masaaki
M
Toda
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