Discovery of Novel Seven-Membered Prostacyclin Analogues as Potent and Selective Prostaglandin FP and EP3 Dual Agonists

  • ACS Med Chem Lett. 2016 Dec 13;8(1):107-112. doi: 10.1021/acsmedchemlett.6b00415.
Isamu Sugimoto  1 ,  Tohru Kambe  2 ,  Tomotaka Okino  2 ,  Tetsuo Obitsu  2 ,  Nobukazu Ohta  2 ,  Taihei Nishiyama  2 ,  Akihiro Kinoshita  2 ,  Taku Fujimoto  2 ,  Hiromu Egashira  2 ,  Shinsaku Yamane  2 ,  Satoshi Shuto  3 ,  Kousuke Tani  2 ,  Toru Maruyama  2
Affiliations
  • 1. 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.
  • 2. 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.
  • 3. 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.
PMID: 28105284 DOI: 10.1021/acsmedchemlett.6b00415
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 derivative 5b, 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 agonist 11b as a lead compound for the development of an antiglaucoma agent.

Keywords
EP3 receptor; FP receptor; GPCR; Prostaglandin; dual agonist; glaucoma.