2,3-Diarylthiophenes as selective EP1 receptor antagonists

2,3-Diarylthiophenes as selective EP1 receptor antagonists

The synthesis and the EP(1) receptor binding affinity of 2,3-diarylthiophene derivatives are described. The evaluation of the structure-activity relationship (SAR) in this series led to the identification of compounds 4, 7, and 12a, which exhibit high affinity for the human EP(1) receptor and a sele...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2005-02, Vol.15 (4), p.1155-1160
Hauptverfasser: DUCHARME, Yves, BLOUIN, Marc, MARTINS, Evelyn, NANTEL, Francois, O'NEILL, Gary, SAWYER, Nicole, METTERS, Kathleen M, FRIESEN, Richard W, CARRIERE, Marie-Claude, CHATEAUNEUF, Anne, COTE, Bernard, DENIS, Danielle, FRENETTE, Richard, GREIG, Gillian, KARGMAN, Stacia, LAMONTAGNE, Sonia
Format: Artikel
Sprache:eng
Schlagworte:
Animals
Biological and medical sciences
Brain - metabolism
Cell Line
Half-Life
Humans
Medical sciences
Miscellaneous
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacokinetics
Pharmacology. Drug treatments
Rats
Receptors, Prostaglandin E - antagonists & inhibitors
Receptors, Prostaglandin E, EP1 Subtype
Structure-Activity Relationship
Thiophenes - chemical synthesis
Thiophenes - pharmacokinetics
Thiophenes - pharmacology
Tissue Distribution
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Zusammenfassung:The synthesis and the EP(1) receptor binding affinity of 2,3-diarylthiophene derivatives are described. The evaluation of the structure-activity relationship (SAR) in this series led to the identification of compounds 4, 7, and 12a, which exhibit high affinity for the human EP(1) receptor and a selectivity greater than 100-fold against the EP(2), EP(3), EP(4), DP, FP, and IP receptors and greater than 25-fold versus the TP receptor. These three antagonists present good pharmacokinetics in rats and significant differences in the way they are distributed in the brain.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2004.12.005