1,5-Biaryl pyrrole derivatives as EP1 receptor antagonists: Structure-activity relationships of 4- and 5-substituted benzoic acid derivatives.
This paper details the SAR of 1,5-biaryl pyrrole derivatives with substituents in the 2-, 4-, and 5-positions of the benzoic acid group as EP1 receptor antagonists. Substitution at the 2-position was poorly tolerated, whereas only fluorine was tolerated at the 4-position. In contrast, a range of substituents at the 5-position were discovered which enhanced the in vitro affinity and led to compounds with promising oral exposure. Three derivatives showed efficacy in a preclinical model of inflammatory pain when dosed orally to rats.
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
D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D010146:Pain / Q000188:drug therapy / Q000209:etiology; 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
D001565:Benzoates; D011758:Pyrroles; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype