RESUMEN
BACKGROUND AND PURPOSE: The discovery of DP2 as a second receptor for PGD2 has prompted the search for antagonists as potential novel therapies based on the associations between PGD2 and disease. Here we describe the biochemical and pharmacological properties of 4-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid (AZD1981), a novel DP2 receptor antagonist. EXPERIMENTAL APPROACH: Binding to DP2 , functional receptor pharmacology and selectivity were studied in both human and animal systems. KEY RESULTS: AZD1981 displaced radio-labelled PGD2 from human recombinant DP2 with high potency (pIC50 = 8.4). Binding was reversible, non-competitive and highly selective against a panel of more than 340 other enzymes and receptors, including DP1 (>1000-fold selective). AZD1981 inhibited DP2 -mediated shape change and CD11b up-regulation in human eosinophils, shape change in basophils and chemotaxis of human eosinophils and Th2 cells with similar potency. AZD1981 exhibited good cross-species binding activity against mouse, rat, guinea pig, rabbit and dog DP2 . Evaluation in mouse, rat or rabbit cell systems was not possible as they did not respond to DP2 agonists. Agonist responses were seen in guinea pig and dog, and AZD1981 blocked DP2 -mediated eosinophil shape change. Such responses were more robust in the guinea pig, where AZD1981 also blocked DP2 -dependent eosinophil emigration from bone marrow. CONCLUSIONS AND IMPLICATIONS: AZD1981 is a DP2 antagonist that blocks functional responses in eosinophils, Th2 cells and basophils. It exhibited similar potency irrespective of the cell type, DP2 agonist or species used. This selective orally active agent is currently under clinical evaluation as a potential therapeutic agent in respiratory diseases including asthma.
Asunto(s)
Acetatos/farmacología , Antiasmáticos/farmacología , Indoles/farmacología , Prostaglandina D2/metabolismo , Receptores de Prostaglandina/antagonistas & inhibidores , Administración Oral , Animales , Basófilos/citología , Basófilos/efectos de los fármacos , Basófilos/fisiología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/fisiología , Antígeno CD11b/metabolismo , Forma de la Célula/efectos de los fármacos , Quimiotaxis de Leucocito/efectos de los fármacos , Perros , Eosinófilos/citología , Eosinófilos/efectos de los fármacos , Eosinófilos/fisiología , Cobayas , Humanos , Técnicas In Vitro , Ratones , Conejos , Ratas , Receptores de Prostaglandina/metabolismo , Especificidad de la Especie , Células Th2/efectos de los fármacos , Células Th2/fisiología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
[reaction: see text]. A user-friendly, one-pot process for catalytic cyclopropanation of alkenes from tosylhydrazones is described. The cyclopropanation of N-vinylphthalimide provides a new route to 2-arylcyclopropylamines, and this is exemplified in the efficient synthesis of the HIV-1 reverse transcriptase inhibitor 6.