title: Identification of novel pyrazole acid antagonists for the EP1 receptor.
abstract: 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.
authors.affiliation: Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. Steve.C.McKeown@gsk.com
authors.forename: Stephen C
authors.initials: SC
authors.lastname: McKeown
authors.forename: Adrian
authors.initials: A
authors.lastname: Hall
authors.forename: Gerard M P
authors.initials: GM
authors.lastname: Giblin
authors.forename: Olivier
authors.initials: O
authors.lastname: Lorthioir
authors.forename: Richard
authors.initials: R
authors.lastname: Blunt
authors.forename: Xiao Q
authors.initials: XQ
authors.lastname: Lewell
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wilson
authors.forename: Susan H
authors.initials: SH
authors.lastname: Brown
authors.forename: Anita
authors.initials: A
authors.lastname: Chowdhury
authors.forename: Tanya
authors.initials: T
authors.lastname: Coleman
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Watson
authors.forename: Iain P
authors.initials: IP
authors.lastname: Chessell
authors.forename: Adrian
authors.initials: A
authors.lastname: Pipe
authors.forename: Nick
authors.initials: N
authors.lastname: Clayton
authors.forename: Paul
authors.initials: P
authors.lastname: Goldsmith
mesh_terms: 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
chemical_list: C545637:Ptger1 protein, rat; D011720:Pyrazoles; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; C031280:pyrazole; D003577:Cytochrome P-450 Enzyme System