title: 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.
abstract: 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.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan. m.asada@ono.co.jp
authors.forename: Masaki
authors.initials: M
authors.lastname: Asada
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Obitsu
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kinoshita
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Nagase
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Yoshida
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamaura
authors.forename: Hiroya
authors.initials: H
authors.lastname: Takizawa
authors.forename: Ken
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Sato
authors.forename: Masami
authors.initials: M
authors.lastname: Narita
authors.forename: Hisao
authors.initials: H
authors.lastname: Nakai
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Tobe
mesh_terms: 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
chemical_list: 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