Identification of novel pyrazole acid antagonists for the EP1 receptor.
The discovery, synthesis and structure-activity relationship (SAR) of a novel series of EP1 receptor antagonists is described. Pyrazole acid 4, identified from a chemical array, had desirable physicochemical properties, an excellent in vitro microsomal inhibition and cytochrome P450 (CYP450) profile and good exposure levels in blood. This compound had an ED50 of 1.3 mg/kg in a rat pain model. A range of more potent analogues in the in vitro assay was identified using efficient array chemistry. These EP1 antagonists have potential as agents in the treatment of PGE2 mediated pain.
McKeown
Stephen C
SC
Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. Steve.C.McKeown@gsk.com
Hall
Adrian
A
Giblin
Gerard M P
GM
Lorthioir
Olivier
O
Blunt
Richard
R
Lewell
Xiao Q
XQ
Wilson
Richard J
RJ
Brown
Susan H
SH
Chowdhury
Anita
A
Coleman
Tanya
T
Watson
Stephen P
SP
Chessell
Iain P
IP
Pipe
Adrian
A
Clayton
Nick
N
Goldsmith
Paul
P
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013329:Structure-Activity Relationship
C545637:Ptger1 protein, rat; D011720:Pyrazoles; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; C031280:pyrazole; D003577:Cytochrome P-450 Enzyme System