The discovery of 6-[2-(5-chloro-2-{[(2,4-difluorophenyl)methyl]oxy}phenyl)-1-cyclopenten-1-yl]-2-pyridinecarboxylic acid, GW848687X, a potent and selective prostaglandin EP1 receptor antagonist for the treatment of inflammatory pain.
The discovery of a series of selective EP1 receptor antagonists based on a 1,2-diarylcyclopentene template is described. After defining the structural requirements for EP1 potency and selectivity, heterocyclic rings were incorporated to reduce logD and improve in vitro pharmacokinetic properties. The 2,6-substituted pyridines and pyridazines gave an appropriate balance of potency, in vivo pharmacokinetic properties and a low potential for inhibiting a range of CYP450 enzymes. From this series, GW848687X was shown to have an excellent profile in models of inflammatory pain and was selected as a development candidate.
Giblin
Gerard M P
GM
Department of Medicinal Chemistry and DMPK, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. ged.m.giblin@gsk.com
Bit
Rino A
RA
Brown
Susan H
SH
Chaignot
Hélène M
HM
Chowdhury
Anita
A
Chessell
Iain P
IP
Clayton
Nicholas M
NM
Coleman
Tanya
T
Hall
Adrian
A
Hammond
Beverley
B
Hurst
David N
DN
Michel
Anton D
AD
Naylor
Alan
A
Novelli
Riccardo
R
Scoccitti
Tiziana
T
Spalding
David
D
Tang
Sac P
SP
Wilson
Alex W
AW
Wilson
Rich
R
D000527:Alprostadil / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005620:Freund's Adjuvant; D006207:Half-Life; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*
C518619:6-(2-(5-chloro-2-(((2,4-difluorophenyl)methyl)oxy)phenyl)-1-cyclopenten-1-yl)-2-pyridinecarboxylic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003517:Cyclopentanes; D011725:Pyridines; D018078:Receptors, Prostaglandin E; D005620:Freund's Adjuvant; D003577:Cytochrome P-450 Enzyme System; D000527:Alprostadil