Structure–activity relationships of 1,5-biaryl pyrroles as EP1 receptor antagonists
| Autor: | Nicholas Maughan Clayton, Gerard Martin Paul Giblin, Mark Patrick Healy, Anton D. Michel, Riccardo Novelli, Beverley Hammond, Stephen John Atkinson, Sac P. Tang, Susan H. Brown, Matthew R. Johnson, Anita Chowdhury, Alan Naylor, David J. Spalding, Adrian Hall, Iain P. Chessell, Robert Gleave, Tanya Coleman |
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| Rok vydání: | 2006 |
| Předmět: |
Stereochemistry
Isostere Carboxylic acid Clinical Biochemistry Biological Availability Pain Pharmaceutical Science Ether Cyclopentanes Ligands Benzoates Biochemistry Chemical synthesis Structure-Activity Relationship chemistry.chemical_compound Cyclohexanes Drug Discovery Animals Receptors Prostaglandin E Pyrroles Molecular Biology Pyrrole Inflammation chemistry.chemical_classification Analgesics Organic Chemistry Receptors Prostaglandin E EP1 Subtype Rats Bioavailability chemistry Benzyl group Molecular Medicine Derivative (chemistry) |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 16:3657-3662 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2006.04.073 |
| Popis: | 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 9.2 mg/kg. |
| Databáze: | OpenAIRE |
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