title: Synthesis and evaluation of γ-lactam analogs of PGE₂ as EP4 and EP2/EP4 agonists.
abstract: To identify topically effective EP4 agonists and EP2/EP4 dual agonists with excellent subtype selectivity, further optimization of the 16-phenyl ω-chain moiety of the γ-lactam 5-thia prostaglandin E analog and the 2-mercaptothiazole-4-carboxylic acid analog were undertaken. Rat in vivo evaluation of these newly identified compounds as their poly (lactide-co-glycolide) microsphere formulation, from which sustained release of the test compound is possible, led us to discover compounds that showed efficacy in a rat bone fracture healing model after its topical administration without serious influence on blood pressure and heart rate. A structure-activity relationship study is also presented.
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: 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; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry; D015232:Dinoprostone / Q000737:chemistry; D004353:Drug Evaluation, Preclinical / Q000379:methods; D017102:Fracture Healing / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007769:Lactams / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008863:Microspheres; D015394:Molecular Structure; D011098:Polyglactin 910 / Q000008:administration & dosage / Q000737:chemistry; D011459:Prostaglandins E, Synthetic / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists*; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000737:chemistry
chemical_list: C573385:2-mercaptothiazole-4-carboxylic acid; D003692:Delayed-Action Preparations; D007769:Lactams; D011459:Prostaglandins E, Synthetic; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D053778:Thiazolidines; D011098:Polyglactin 910; D015232:Dinoprostone