title: Discovery of highly potent dual EP(2) and EP(3) agonists with subtype selectivity.
abstract: The cyclic carbamate derivatives, 2-{[2-((4S)-4-{(1E,3R)-8-fluoro-3-hydroxy-4,4-dimethyl-1-octenyl}-2-oxo-1,3-oxazolidin-3-yl)ethyl]sulfanyl}-1,3-thiazole-4-carboxylic acid (5) and 2-{[2-((4S)-4-{(1E,3R)-3-[1-(4-fluorobutyl)cyclobutyl]-3-hydroxy-1-propenyl}-2-oxo-1,3-oxazolidin-3-yl)ethyl]sulfanyl}-1,3-thiazole-4-carboxylic acid (7) were identified as the first potent dual EP2 and EP3 agonists with selectivity against the EP1 and EP4 subtypes. Compounds 5 and 7 demonstrated highly potent dual EP2 and EP3 agonist activity with EC50 values of 10nM or less. In addition, these compounds possess structural features distinct from natural prostaglandins, such as a cyclic carbamate moiety, a dimethyl or cyclobutyl group and a terminal fluorine atom.
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan. Electronic address: ak.kinoshita@ono.co.jp.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kinoshita
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Higashino
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Aratani
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Kakuuchi
authors.affiliation: Department of Biology & Pharmacology, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Matsuya
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan. Electronic address: k.ohmoto@ono.co.jp.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Ohmoto
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D051379:Mice; D011485:Protein Binding; D051381:Rats; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000819:agonists / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists* / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000819:agonists* / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype
keywords: Dual agonist; EP(2) receptor; EP(3) receptor; Prostaglandin; Underactive bladder