Substituted indole-1-acetic acids as potent and selective CRTh2 antagonists-discovery of AZD1981.

Medicinal Chemistry, AstraZeneca R&D Charnwood, Loughborough, Leicestershire LE11 5RH, UK.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.65). 09/2011; 21(21):6288-92. DOI: 10.1016/j.bmcl.2011.08.124
Source: PubMed

ABSTRACT Novel indole-3-thio-, 3-sulfonyl- and 3-oxy-aryl-1-acetic acids are reported which are potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). Optimization required maintenance of high CRTh2 potency whilst achieving a concomitant reduction in rates of metabolism, removal of cyp p450 inhibition and minimization of aldose reductase and aldehyde reductase activity. High quality compounds suitable for in vivo studies are highlighted, culminating in the discovery of AZD1981 (22).

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    ABSTRACT: BACKGROUND AND PURPOSE: The discovery of CRTh2 as a second receptor for prostaglandin D(2) (PGD(2) ) has prompted the search for antagonists as potential novel therapies based on the associations between PGD(2) 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 CRTh2 antagonist. EXPERIMENTAL APPROACH: Binding to CRTh2, functional receptor pharmacology and selectivity were studied in both human and animal systems. KEY RESULTS: AZD1981 displaced radio-labelled PGD(2) from human recombinant CRTh2 with high potency (pIC(50) = 8.4). Binding was reversible, non-competitive and highly selective against a panel of more than 340 other enzymes and receptors, including DP(1) (>1000-fold selective). AZD1981 inhibited CRTh2-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 CRTh2. Evaluation in mouse, rat or rabbit cell systems was not possible as they did not respond to CRTh2 agonists. Agonist responses were seen in guinea-pig and dog and AZD1981 blocked CRTh2-mediated eosinophil shape change. Such responses were more robust in the guinea-pig, where AZD1981 also blocked CRTh2-dependent eosinophil emigration from bone marrow. CONCLUSIONS AND IMPLICATIONS: AZD1981 is a CRTh2 antagonist that blocks functional responses in eosinophils, Th2 cells and basophils. It exhibited similar potency irrespective of the cell type, CRTh2 agonist or species used. This selective orally active agent is currently under clinical evaluation as a potential therapeutic agent in respiratory diseases including asthma.
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