Discovery and characterization of a potent and selective EP4 receptor antagonist

[Display omitted] EP4 is a prostaglandin E2 receptor that is a target for potential anti-nociceptive therapy. Described herein is a class of amphoteric EP4 antagonists which reverses PGE2-induced suppression of TNFα production in human whole blood. From this class, a potent and highly bioavailable c...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2015-08, Vol.25 (16), p.3176-3178
Hauptverfasser:	Schiffler, Matthew A., Chandrasekhar, Srinivasan, Fisher, Matthew J., Harvey, Anita, Kuklish, Steven L., Wang, Xu-Shan, Warshawsky, Alan M., York, Jeremy S., Yu, Xiao-Peng
Format:	Artikel
Sprache:	eng
Schlagworte:	Amphoteric Analgesics - chemistry Analgesics - metabolism Analgesics - pharmacokinetics Animals Blood Cells - cytology Blood Cells - drug effects Blood Cells - metabolism Dog bioavailability Dogs EP4 antagonist Half-Life Humans Lipopolysaccharides - toxicity Prostaglandin pathway Protein Binding Receptors, Prostaglandin E, EP4 Subtype - antagonists & inhibitors Receptors, Prostaglandin E, EP4 Subtype - metabolism Structure-Activity Relationship Tumor Necrosis Factor-alpha - metabolism
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Zusammenfassung:	[Display omitted] EP4 is a prostaglandin E2 receptor that is a target for potential anti-nociceptive therapy. Described herein is a class of amphoteric EP4 antagonists which reverses PGE2-induced suppression of TNFα production in human whole blood. From this class, a potent and highly bioavailable compound (6) has been selected for potential clinical studies. EP4 binding and functional data, selectivity, and pharmacokinetic properties of this compound are included.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2015.05.091