Structure-activity relationships of 1,5-biaryl pyrroles as EP1 receptor antagonists.
The preliminary SAR of a series of novel 1,5-biaryl pyrrole EP1 receptor antagonists derived from compound 1 is described. Replacement of the benzyl group of 1 with isosteric groups was investigated. The most effective replacement was found to be the isobutyl group. The cyclopentylmethyl and cyclohexylmethyl groups were also effective benzyl replacements. The cyclohexylmethyl derivative 19 demonstrated the lowest metabolic clearance within this series. In addition, several high affinity substituted benzyl analogues were also identified. Compound 39 was found to have good bioavailability in rats and demonstrated efficacy in the established FCA preclinical model of inflammatory pain with a calculated ED50 of 9.2mg/kg.
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
Atkinson
Stephen
S
Brown
Susan H
SH
Chessell
Iain P
IP
Chowdhury
Anita
A
Clayton
Nicholas M
NM
Coleman
Tanya
T
Giblin
Gerard M P
GM
Gleave
Robert J
RJ
Hammond
Beverley
B
Healy
Mark P
MP
Johnson
Matthew R
MR
Michel
Anton D
AD
Naylor
Alan
A
Novelli
Riccardo
R
Spalding
David J
DJ
Tang
Sac P
SP
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis / Q000494:pharmacology*; D001682:Biological Availability; D003510:Cyclohexanes / Q000737:chemistry; D003517:Cyclopentanes / Q000737:chemistry; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008024:Ligands; D010146:Pain / Q000188:drug therapy / Q000473:pathology; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013329:Structure-Activity Relationship
D000700:Analgesics; D001565:Benzoates; D003510:Cyclohexanes; D003517:Cyclopentanes; D008024:Ligands; D011758:Pyrroles; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype