Linier Shape @ EP2 Agonists

The Articles Shows Linear Open Shape of
Eicosanoids As An Agonists;

Discovery of G Protein-Biased EP2 Receptor Agonists

Seiji Ogawa^*†^∥, Toshihide Watanabe†, Isamu Sugimoto†, Kazumi Moriyuki‡, Yoshikazu Goto‡, Shinsaku Yamane‡, Akio Watanabe†, Kazuma Tsuboi†, Atsushi Kinoshita†, Hideo Kigoshi^∥, Kousuke Tani§, and Toru Maruyama†

^†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

ACS Med. Chem. Lett., 2016, 7 (3), pp 306–311

DOI: 10.1021/acsmedchemlett.5b00455

Publication Date (Web): January 4, 2016

Copyright © 2016 American Chemical Society

*Tel: +81-75-961-1151. Fax: +81-75-962-9314. E-mail: s.ogawa@ono.co.jp.

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:

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

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.5b00455.

• Experimental procedures of compounds, characterization data, and conditions of the biological assays (PDF)

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