Non-acidic pyrazole EP1 receptor antagonists with in vivo analgesic efficacy.
Replacement of the carboxylic acid group in a series of previously described methylene-linked pyrazole EP(1) receptor antagonists led to the discovery of amide, reversed amide and carbamate derivatives. Two compounds, 10a and 10b, were identified as brain penetrant compounds and both demonstrated efficacy in the CFA model of inflammatory pain.
Hall
Adrian
A
Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK. adrian.2.hall@gsk.com
Billinton
Andy
A
Brown
Susan H
SH
Clayton
Nicholas M
NM
Chowdhury
Anita
A
Giblin
Gerard M P
GM
Goldsmith
Paul
P
Hayhow
Thomas G
TG
Hurst
David N
DN
Kilford
Ian R
IR
Naylor
Alan
A
Passingham
Barry
B
Winyard
Lisa
L
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D010147:Pain Measurement; D011720:Pyrazoles / Q000138:chemical synthesis* / 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; D011720:Pyrazoles; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype