Discovery of G Protein-Biased EP2 Receptor Agonists

作者：Ogawa Seiji^*; Watanabe Toshihide; Sugimoto Isamu; Moriyuki Kazumi; Goto Yoshikazu; Yamane Shinsaku; Watanabe Akio; Tsuboi Kazuma; Kinoshita Atsushi; Kigoshi Hideo; Tani Kousuke; Maruyama Toru

来源：ACS Medicinal Chemistry Letters, 2016, 7(3): 306-311.

DOI：10.1021/acsmedchemlett.5b00455

• Prostaglandin
• EP2
• agonist
• biased ligand
• structure-functional selectivity relationship

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 omega chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the omega 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.

• 出版日期2016-3