Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 7, Issue 3, Pages 306-311Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.5b00455
Keywords
Prostaglandin; EP2; agonist; biased ligand; structure-functional selectivity relationship
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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.
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