title: Design and synthesis of a selective EP4-receptor agonist. Part 1: discovery of 3,7-dithiaPGE1 derivatives and identification of their omega chains.
abstract: Improvement of EP4-receptor selectivity and the agonist activity by introduction of heteroatoms into the alpha chain of PGE1 was investigated. Among the compounds tested, 3,7-dithiaPGE1 4a exhibited good EP4-receptor selectivity and agonist activity. Further modification of the omega chain of 3,7-dithiaPGE1 was performed to improve EP4-receptor selectivity and agonist activity. Of the compounds produced, 16-phenyl-omega-tetranor-3,7-dithiaPGE1 4p possessing moderate EP4-receptor selectivity and agonist activity, was identified as a new chemical lead for further optimization by modification of the aromatic moiety.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd., Shimamoto, Mishima, 618-8585, Osaka, Japan. to.maruyama@ono.co.jp
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
authors.forename: Masaki
authors.initials: M
authors.lastname: Asada
authors.forename: Tai
authors.initials: T
authors.lastname: Shiraishi
authors.forename: Hiromu
authors.initials: H
authors.lastname: Egashira
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yoshida
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: D000527:Alprostadil / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000032:analysis; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D011485:Protein Binding; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013329:Structure-Activity Relationship; D013440:Sulfides
chemical_list: C464981:3,7-dithia(11 alpha,13E,15S)-11,15-Dihydroxy-9-oxoprost-13-en-1-oic acid; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013440:Sulfides; D000242:Cyclic AMP; D000527:Alprostadil; D002118:Calcium