1,5-Biaryl pyrrole derivatives as EP1 receptor antagonists. Structure-activity relationships of 6-substituted and 5,6-disubstituted benzoic acid derivatives.
Herein we describe the SAR of 1,5-biaryl pyrrole derivatives, with substituents in the 6-position of the benzoic acid moiety, as EP(1) receptor antagonists. Substitution at this position was well tolerated and led to the identification of several analogues with high affinity for the EP(1) receptor that displayed good efficacy in the established FCA model of inflammatory pain. Furthermore, several analogues were prepared which combined substitution at the 5- and 6-positions as well as derivatives with an aromatic ring fused to the 5- and 6-positions.
Hall
Adrian
A
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. adrian.2.hall@gsk.com
Brown
Susan H
SH
Chessell
Iain P
IP
Chowdhury
Anita
A
Clayton
Nicholas M
NM
Coleman
Tanya
T
Giblin
Gerard M P
GM
Hammond
Beverley
B
Healy
Mark P
MP
Johnson
Matthew R
MR
Metcalf
Ann
A
Michel
Anton D
AD
Naylor
Alan
A
Novelli
Riccardo
R
Spalding
David J
DJ
Sweeting
Jennifer
J
Winyard
Lisa
L
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001565:Benzoates / Q000138:chemical synthesis* / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D007202:Indicators and Reagents; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D001565:Benzoates; D007202:Indicators and Reagents; C545635:PTGER1 protein, human; D011758:Pyrroles; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D003577:Cytochrome P-450 Enzyme System