Document Detail

Structure-activity relationships of 1,5-biaryl pyrroles as EP1 receptor antagonists.
MedLine Citation:
PMID:  16697196     Owner:  NLM     Status:  MEDLINE    
The preliminary SAR of a series of novel 1,5-biaryl pyrrole EP1 receptor antagonists derived from compound 1 is described. Replacement of the benzyl group of 1 with isosteric groups was investigated. The most effective replacement was found to be the isobutyl group. The cyclopentylmethyl and cyclohexylmethyl groups were also effective benzyl replacements. The cyclohexylmethyl derivative 19 demonstrated the lowest metabolic clearance within this series. In addition, several high affinity substituted benzyl analogues were also identified. Compound 39 was found to have good bioavailability in rats and demonstrated efficacy in the established FCA preclinical model of inflammatory pain with a calculated ED50 of 9.2mg/kg.
Adrian Hall; Stephen Atkinson; Susan H Brown; Iain P Chessell; Anita Chowdhury; Nicholas M Clayton; Tanya Coleman; Gerard M P Giblin; Robert J Gleave; Beverley Hammond; Mark P Healy; Matthew R Johnson; Anton D Michel; Alan Naylor; Riccardo Novelli; David J Spalding; Sac P Tang
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Publication Detail:
Type:  Journal Article     Date:  2006-05-11
Journal Detail:
Title:  Bioorganic & medicinal chemistry letters     Volume:  16     ISSN:  0960-894X     ISO Abbreviation:  Bioorg. Med. Chem. Lett.     Publication Date:  2006 Jul 
Date Detail:
Created Date:  2006-06-05     Completed Date:  2006-09-25     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9107377     Medline TA:  Bioorg Med Chem Lett     Country:  England    
Other Details:
Languages:  eng     Pagination:  3657-62     Citation Subset:  IM    
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
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MeSH Terms
Analgesics / pharmacology*
Benzoates / chemical synthesis,  pharmacology*
Biological Availability
Cyclohexanes / chemistry
Cyclopentanes / chemistry
Inflammation / drug therapy,  pathology
Pain / drug therapy,  pathology
Pyrroles / chemistry,  pharmacology*
Receptors, Prostaglandin E / antagonists & inhibitors*
Structure-Activity Relationship
Reg. No./Substance:
0/Analgesics; 0/Benzoates; 0/Cyclohexanes; 0/Cyclopentanes; 0/Ligands; 0/Pyrroles; 0/Receptors, Prostaglandin E; 0/prostanoid receptor EP1

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