Discovery of G Protein-Biased EP2 Receptor Agonists

  • ACS Med Chem Lett. 2016 Jan 4;7(3):306-11. doi: 10.1021/acsmedchemlett.5b00455.
Seiji Ogawa  1 ,  Toshihide Watanabe  2 ,  Isamu Sugimoto  2 ,  Kazumi Moriyuki  2 ,  Yoshikazu Goto  2 ,  Shinsaku Yamane  2 ,  Akio Watanabe  2 ,  Kazuma Tsuboi  2 ,  Atsushi Kinoshita  2 ,  Hideo Kigoshi  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; Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8571, 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. Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba , 1-1-1 Tennodai, Tsukuba 305-8571, Japan.
PMID: 26985320 DOI: 10.1021/acsmedchemlett.5b00455
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.

Keywords
EP2; Prostaglandin; agonist; biased ligand; structure−functional selectivity relationship.
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