Discovery of G Protein-Biased EP2 Receptor Agonists
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- 作者：Seiji Ogawa ; Toshihide Watanabe ; Isamu Sugimoto ; Kazumi Moriyuki ; Yoshikazu Goto ; Shinsaku Yamane ; Akio Watanabe ; Kazuma Tsuboi ; Atsushi Kinoshita ; Hideo Kigoshi ; Kousuke Tani ; Toru Maruyama
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：March 10, 2016
- 年：2016
- 卷：7
- 期：3
- 页码：306-311
- 全文大小：343K
- ISSN：1948-5875
文摘
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.