title: 2,3-Diarylthiophenes as selective EP1 receptor antagonists.
abstract: 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.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Québec, Canada H9R 4P8. yves_ducgarme@merck.com
authors.forename: Yves
authors.initials: Y
authors.lastname: Ducharme
authors.forename: Marc
authors.initials: M
authors.lastname: Blouin
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Carrière
authors.forename: Anne
authors.initials: A
authors.lastname: Chateauneuf
authors.forename: Bernard
authors.initials: B
authors.lastname: Côté
authors.forename: Danielle
authors.initials: D
authors.lastname: Denis
authors.forename: Richard
authors.initials: R
authors.lastname: Frenette
authors.forename: Gillian
authors.initials: G
authors.lastname: Greig
authors.forename: Stacia
authors.initials: S
authors.lastname: Kargman
authors.forename: Sonia
authors.initials: S
authors.lastname: Lamontagne
authors.forename: Evelyn
authors.initials: E
authors.lastname: Martins
authors.forename: François
authors.initials: F
authors.lastname: Nantel
authors.forename: Gary
authors.initials: G
authors.lastname: O'Neill
authors.forename: Nicole
authors.initials: N
authors.lastname: Sawyer
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Metters
authors.forename: Richard W
authors.initials: RW
authors.lastname: Friesen
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D006207:Half-Life; D006801:Humans; D010599:Pharmacokinetics; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: C545635:PTGER1 protein, human; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013876:Thiophenes