3-(2-Aminocarbonylphenyl)propanoic acid analogs as potent and selective EP3 receptor antagonists. Part 3: Synthesis, metabolic stability, and biological evaluation of optically active analogs.
A series of 3-(2-aminocarbonylphenyl)propanoic acid analogs possessing the (1R)-1-(3,5-dimethylphenyl)-3-methylbutylamine moiety on the carboxyamide side chain were synthesized and evaluated for their binding affinity for the EP1-4 receptors and their antagonist activity for the EP3 receptor. Rational drug design based on the structure of the metabolites in human liver microsomes led us to the discovery of another series of analogs. Several compounds were further evaluated for their in vivo efficacy in rats after oral administration and also for their pharmacokinetic profiles including in vitro stability in the liver microsomes.
Asada
Masaki
M
Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan. m.asada@ono.co.jp
Obitsu
Tetsuo
T
Kinoshita
Atsushi
A
Nagase
Toshihiko
T
Yoshida
Tadahiro
T
Yamaura
Yoshiyuki
Y
Takizawa
Hiroya
H
Yoshikawa
Ken
K
Sato
Kazutoyo
K
Narita
Masami
M
Nakai
Hisao
H
Toda
Masaaki
M
Tobe
Yoshito
Y
D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004355:Drug Stability; D005260:Female; D006801:Humans; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D010647:Phenyl Ethers; D011247:Pregnancy; D011270:Pregnancy, Animal; D011422:Propionates / Q000138:chemical synthesis / Q000737:chemistry; D011869:Radioligand Assay; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype
C548852:3-(2-aminocarbonyl-4-phenoxymethylphenyl)propanoic acid; C545647:PTGER3 protein, human; D010647:Phenyl Ethers; D011422:Propionates; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype