title: Discovery of novel prostaglandin analogs as potent and selective EP2/EP4 dual agonists.
abstract: To identify potent EP2/EP4 dual agonists with excellent subtype selectivity, a series of γ-lactam prostaglandin E analogs bearing a 16-phenyl ω-chain were synthesized and evaluated. Structural hybridization of 1 and 2, followed by more detailed chemical modification of the benzoic acid moiety, led us to the discovery of a 2-mercaptothiazole-4-carboxylic acid analog 3 as the optimal compound in the series. An isomer of this compound, the 2-mercaptothiazole-5-carboxylic acid analog 13, showed 34-fold and 13-fold less potent EP2 and EP4 receptor affinities, respectively. Structure activity relationship data from an in vitro mouse receptor binding assay are presented. Continued evaluation in an in vivo rat model of another 2-mercaptothiazole-4-carboxylic acid analog 17, optimized for sustained compound release from PLGA microspheres, demonstrated its effectiveness in a rat bone fracture-healing model following topical administration.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd., Shimamoto, Mishima, Osaka 618-8585, Japan. kanbe@ono.co.jp
authors.forename: Tohru
authors.initials: T
authors.lastname: Kambe
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Nakai
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yoshida
authors.forename: Hiroji
authors.initials: H
authors.lastname: Oida
authors.forename: Takayuki
authors.initials: T
authors.lastname: Maruyama
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Abe
authors.forename: Akio
authors.initials: A
authors.lastname: Nishiura
authors.forename: Hisao
authors.initials: H
authors.lastname: Nakai
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
mesh_terms: D000287:Administration, Topical; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D050723:Fractures, Bone / Q000188:drug therapy; D007536:Isomerism; D051379:Mice; D011465:Prostaglandins, Synthetic / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D051381:Rats; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: C573385:2-mercaptothiazole-4-carboxylic acid; D011465:Prostaglandins, Synthetic; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D053778:Thiazolidines