title: Discovery of G Protein-Biased EP2 Receptor Agonists.
abstract: To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the ω chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors.
authors.affiliation: Medicinal Chemistry Research Laboratories, Department of Biology & Pharmacology, and Discovery Research Alliance, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan; Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8571, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Medicinal Chemistry Research Laboratories, Department of Biology & Pharmacology, and Discovery Research Alliance, Ono Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Medicinal Chemistry Research Laboratories, Department of Biology & Pharmacology, and Discovery Research Alliance, Ono Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Isamu
authors.initials: I
authors.lastname: Sugimoto
authors.affiliation: Medicinal Chemistry Research Laboratories, Department of Biology & Pharmacology, and Discovery Research Alliance, Ono Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Moriyuki
authors.affiliation: Medicinal Chemistry Research Laboratories, Department of Biology & Pharmacology, and Discovery Research Alliance, Ono Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Goto
authors.affiliation: Medicinal Chemistry Research Laboratories, Department of Biology & Pharmacology, and Discovery Research Alliance, Ono Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Yamane
authors.affiliation: Medicinal Chemistry Research Laboratories, Department of Biology & Pharmacology, and Discovery Research Alliance, Ono Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Medicinal Chemistry Research Laboratories, Department of Biology & Pharmacology, and Discovery Research Alliance, Ono Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Tsuboi
authors.affiliation: Medicinal Chemistry Research Laboratories, Department of Biology & Pharmacology, and Discovery Research Alliance, Ono Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kinoshita
authors.affiliation: Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba , 1-1-1 Tennodai, Tsukuba 305-8571, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Kigoshi
authors.affiliation: Medicinal Chemistry Research Laboratories, Department of Biology & Pharmacology, and Discovery Research Alliance, Ono Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Tani
authors.affiliation: Medicinal Chemistry Research Laboratories, Department of Biology & Pharmacology, and Discovery Research Alliance, Ono Pharmaceutical Co., Ltd. , 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
keywords: EP2; Prostaglandin; agonist; biased ligand; structure−functional selectivity relationship