Discovery of a new class of potent, selective, and orally bioavailable CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases
| Autor: | Alexander Scheer, Jean-François Arrighi, Lucia Golzio, Marc Missotten, Yaroslav Filinchuk, Véronique Colovray, Pierre-André Pittet, Christophe Cleva, André Chollet, Thierry Martin, Atherall John Frederick, Claudio Giachetti, Maurizio Maio, Cynthia Rocha, Matthias Schwarz, Jackie Macritchie, Patrick Page, Gérald Bernardinelli, Stefano Crosignani, Yves Humbert, Doris Pupowicz, Marilène Gaudet |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Models Molecular Cell Membrane Permeability Indoles Receptors Prostaglandin Crystallography X-Ray Chemical synthesis Rats Sprague-Dawley chemistry.chemical_compound Structure-Activity Relationship Dogs In vivo Microsomes Drug Discovery Hypersensitivity Potency Structure–activity relationship Animals Cytochrome P-450 Enzyme Inhibitors Humans Spiro Compounds Receptors Immunologic Receptor Inflammation Binding Sites Molecular Structure Chemotaxis Stereoisomerism Rats chemistry Biochemistry Drug Design Eosinophil chemotaxis Molecular Medicine Prostaglandin D2 Caco-2 Cells |
| Zdroj: | Journal of medicinal chemistry. 51(7) |
| ISSN: | 0022-2623 |
| Popis: | A novel chemical class of potent chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTH2 or DP2) antagonists is reported. An initial and moderately potent spiro-indolinone compound (5) was found during a high-throughput screening campaign. Structure-activity relationship (SAR) investigation around the carboxylic acid group revealed that changes in this part of the molecule could lead to a reversal of functional activity, yielding weakly potent agonists. SAR investigation of the succinimide functional group led to the discovery of several single-digit nanomolar antagonists. The potency of these compounds was confirmed in a human eosinophil chemotaxis assay. Moreover, compounds (R)-58 and (R)-71 were shown to possess pharmacokinetic properties suitable for development as an orally bioavailable drug. © 2008 American Chemical Society. |
| Databáze: | OpenAIRE |
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