title: Discovery of Novel Seven-Membered Prostacyclin Analogues as Potent and Selective Prostaglandin FP and EP3 Dual Agonists.
abstract: A novel series of prostaglandin analogues with a seven-membered ring scaffold was designed, synthesized, and evaluated for the functional activation of prostaglandin receptors to identify potent and subtype-selective FP and EP3 dual agonists. Starting from the prostacyclin derivative5b, a nonselective agonist for prostaglandin receptors, replacement of the core structure with an octahydro-2H-cyclopenta[b]oxepine scaffold led to the discovery of the potent and selective FP and EP3 dual agonist11bas a lead compound for the development of an antiglaucoma agent.
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; Faculty of Pharmaceutical Sciences and Center for Research and Education on Drug Discovery, Hokkaido University, Kita-12, Nishi-6, Kita-Ku, Sapporo 060-0812, 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: Tohru
authors.initials: T
authors.lastname: Kambe
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: Tomotaka
authors.initials: T
authors.lastname: Okino
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: Tetsuo
authors.initials: T
authors.lastname: Obitsu
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: Nobukazu
authors.initials: N
authors.lastname: Ohta
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: Taihei
authors.initials: T
authors.lastname: Nishiyama
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: Akihiro
authors.initials: A
authors.lastname: Kinoshita
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: Taku
authors.initials: T
authors.lastname: Fujimoto
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: Hiromu
authors.initials: H
authors.lastname: Egashira
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: Faculty of Pharmaceutical Sciences and Center for Research and Education on Drug Discovery, Hokkaido University, Kita-12, Nishi-6, Kita-Ku, Sapporo 060-0812, Japan; Faculty of Pharmaceutical Sciences and Center for Research and Education on Drug Discovery, Hokkaido University, Kita-12, Nishi-6, Kita-Ku, Sapporo 060-0812, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
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: EP3 receptor; FP receptor; GPCR; Prostaglandin; dual agonist; glaucoma