Discovery of GSK345931A: An EP(1) receptor antagonist with efficacy in preclinical models of inflammatory pain.
Herein we describe the medicinal chemistry programme to identify a potential back-up compound to the EP(1) receptor antagonist GW848687X. This work started with the lipophilic 1,2-biaryl benzene derivative 4 which displayed molecular weight of 414.9g/mol and poor in vivo metabolic stability in the rat and resulted in the identification of compound 7i (GSK345931A) which demonstrated good metabolic stability in the rat and lower molecular weight (381.9g/mol). In addition, 7i (GSK345931A) showed measurable CNS penetration in the mouse and rat and potent analgesic efficacy in acute and sub-chronic models of inflammatory pain.
Hall
Adrian
A
Neurosciences 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
Budd
Christopher
C
Clayton
Nicholas M
NM
Giblin
Gerard M P
GM
Goldsmith
Paul
P
Hayhow
Thomas G
TG
Hurst
David N
DN
Naylor
Alan
A
Anthony Rawlings
D
D
Scoccitti
Tiziana
T
Wilson
Alexander W
AW
Winchester
Wendy J
WJ
D000818:Animals; D004353:Drug Evaluation, Preclinical; D007249:Inflammation / Q000188:drug therapy*; D010146:Pain / Q000188:drug therapy*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013329:Structure-Activity Relationship
C538709:GSK345931A; C545636:Ptger1 protein, mouse; C545637:Ptger1 protein, rat; D011725:Pyridines; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype