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Discovery of G Protein-Biased EP2 Receptor Agonists.

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

SUBMITTER: Ogawa S

PROVIDER: S-EPMC4789666 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Discovery of G Protein-Biased EP2 Receptor Agonists.

Ogawa Seiji S Watanabe Toshihide T Sugimoto Isamu I Moriyuki Kazumi K Goto Yoshikazu Y Yamane Shinsaku S Watanabe Akio A Tsuboi Kazuma K Kinoshita Atsushi A Kigoshi Hideo H Tani Kousuke K Maruyama Toru T

ACS medicinal chemistry letters 20160104 3

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 po ...[more]

PMID: 26985320

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