1,5-Biaryl pyrrole derivatives as EP1 receptor antagonists : Structure-activity relationships of 4-and 5-substituted benzoic acid derivatives

This paper details the SAR of 1,5-biaryl pyrrole derivatives with substituents in the 2-, 4-, and 5-positions of the benzoic acid group as EP1 receptor antagonists. Substitution at the 2-position was poorly tolerated, whereas only fluorine was tolerated at the 4-position. In contrast, a range of sub...

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Bibliographic Details
Published inBioorganic & medicinal chemistry letters Vol. 17; no. 3; pp. 732 - 735
Main Authors HALL, Adrian, BROWN, Susan H, METCALF, Ann, MICHEL, Anton D, NAYLOR, Alan, NOVELLI, Riccardo, SPALDING, David J, SWEETING, Jennifer, CHESSELL, Iain P, CHOWDHURY, Anita, CLAYTON, Nicholas M, COLEMAN, Tanya, GIBLIN, Gerard M. P, HAMMOND, Beverley, HEALY, Mark P, JOHNSON, Matthew R
Format Journal Article
LanguageEnglish
Published Oxford Elsevier 01.02.2007
Subjects
Analgesics
Animals
Benzoates - chemical synthesis
Benzoates - chemistry
Benzoates - pharmacology
Biological and medical sciences
CHO Cells
Cricetinae
Cricetulus
Inflammation - chemically induced
Inflammation - complications
Medical sciences
Neuropharmacology
Pain - drug therapy
Pain - etiology
Pharmacology. Drug treatments
Pyrroles - chemical synthesis
Pyrroles - pharmacology
Rats
Receptors, Prostaglandin E - antagonists & inhibitors
Receptors, Prostaglandin E, EP1 Subtype
Structure-Activity Relationship
Rat
Pyrrole derivatives
Benzoic acid derivatives
Pain
Structure activity relation
Established FCA
Antagonist
Chemical synthesis
Rodentia
Oral administration
Organic bromine compounds
Inflammation
In vitro
EP1 prostanoid receptor
In vivo
Vertebrata
Mammalia
Analgesic
Animal
Organic fluorine compounds
Pyrrole
Affinity
Models
EP1 antagonist
Pharmacokinetics
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Summary:This paper details the SAR of 1,5-biaryl pyrrole derivatives with substituents in the 2-, 4-, and 5-positions of the benzoic acid group as EP1 receptor antagonists. Substitution at the 2-position was poorly tolerated, whereas only fluorine was tolerated at the 4-position. In contrast, a range of substituents at the 5-position were discovered which enhanced the in vitro affinity and led to compounds with promising oral exposure. Three derivatives showed efficacy in a preclinical model of inflammatory pain when dosed orally to rats.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2006.10.078