title: Development of a highly selective EP2-receptor agonist. Part 2: identification of 16-hydroxy-17,17-trimethylene 9beta-chloro PGF derivatives.
abstract: Further chemical modification of 1a and 2 was undertaken to identify a more chemically stable selective EP2-receptor agonist for development as a clinical candidate. 9beta-chloro PG analogues 4a-e and 5a, c-e were found to be potent and selective EP2-receptor agonists. Among them, the compound 4aLy, which is a chemically stabilized lysine salt of 4a, exhibited an excellent profile both in biological activities and physicochemical properties. The agonist 4aLy was found to suppress uterine motility in anesthetized pregnant rats, while PGE2 stimulated uterine motility. Structure-activity relationships (SARs) are discussed.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd., Shimamoto, Mishima, 618-8585, Osaka, Japan. k.tani@ono.co.jp
authors.forename: Kousuke
authors.initials: K
authors.lastname: Tani
authors.forename: Atsushi
authors.initials: A
authors.lastname: Naganawa
authors.forename: Akiharu
authors.initials: A
authors.lastname: Ishida
authors.forename: Hiromu
authors.initials: H
authors.lastname: Egashira
authors.forename: Kenji
authors.initials: K
authors.lastname: Sagawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Harada
authors.forename: Mikio
authors.initials: M
authors.lastname: Ogawa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Maruyama
authors.forename: Shuichi
authors.initials: S
authors.lastname: Ohuchida
authors.forename: Hisao
authors.initials: H
authors.lastname: Nakai
authors.forename: Kigen
authors.initials: K
authors.lastname: Kondo
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004355:Drug Stability; D005260:Female; D011247:Pregnancy; D011461:Prostaglandins F, Synthetic / Q000138:chemical synthesis / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000819:agonists*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014590:Uterine Contraction / Q000187:drug effects
chemical_list: D011461:Prostaglandins F, Synthetic; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D000242:Cyclic AMP