title: Discovery of a novel EP2/EP4 dual agonist with high subtype-selectivity.
abstract: A series of γ-lactam prostaglandin E(1) analogs bearing a 16-phenyl moiety in the ω-chain and aryl moiety in the α-chain were synthesized and biologically evaluated. Among the tested compounds, γ-lactam PGE analog 3 designed as a structural hybrid of 1 and 2 was discovered as the most optimized EP2/EP4 dual agonist with excellent subtype-selectivity (K(i) values: mEP2=9.3 nM, mEP4=0.41 nM). A structure-activity relationship study is presented.
authors: Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan. kanbe@ono.co.jp
authors: Tohru
authors: T
authors: Kambe
authors: Toru
authors: T
authors: Maruyama
authors: Masayuki
authors: M
authors: Nakano
authors: Yoshihiko
authors: Y
authors: Nakai
authors: Tadahiro
authors: T
authors: Yoshida
authors: Naoki
authors: N
authors: Matsunaga
authors: Hiroji
authors: H
authors: Oida
authors: Akira
authors: A
authors: Konaka
authors: Takayuki
authors: T
authors: Maruyama
authors: Hisao
authors: H
authors: Nakai
authors: Masaaki
authors: M
authors: Toda
mesh_terms: D000527:Alprostadil / Q000031:analogs & derivatives*; D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D007769:Lactams / Q000737:chemistry*; D008956:Models, Chemical; D008968:Molecular Conformation; D051381:Rats; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000737:chemistry*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000737:chemistry*
chemical_list: D002264:Carboxylic Acids; D007769:Lactams; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000527:Alprostadil