Document Detail


Biochemical and pharmacological characterization of AZD1981, an orally available selective DP2 antagonist in clinical development for asthma.
MedLine Citation:
PMID:  23146091     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
J A Schmidt; F M Bell; E Akam; C Marshall; I A Dainty; A Heinemann; I G Dougall; R V Bonnert; C A Sargent
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  168     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-11-25     Revised Date:  2014-04-01    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1626-38     Citation Subset:  IM    
Copyright Information:
© 2012 AstraZeneca R&D Charnwood. British Journal of Pharmacology © 2012 The British Pharmacological Society.
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MeSH Terms
Descriptor/Qualifier:
Acetates / pharmacology*
Administration, Oral
Animals
Anti-Asthmatic Agents / pharmacology*
Antigens, CD11b / metabolism
Basophils / cytology,  drug effects,  physiology
Bone Marrow Cells / drug effects,  physiology
Cell Shape / drug effects
Chemotaxis, Leukocyte / drug effects
Dogs
Eosinophils / cytology,  drug effects,  physiology
Guinea Pigs
Humans
Indoles / pharmacology*
Mice
Prostaglandin D2 / metabolism*
Rabbits
Rats
Receptors, Prostaglandin / antagonists & inhibitors*,  metabolism
Species Specificity
Th2 Cells / drug effects,  physiology
Up-Regulation / drug effects
Chemical
Reg. No./Substance:
0/AZD1981; 0/Acetates; 0/Anti-Asthmatic Agents; 0/Antigens, CD11b; 0/Indoles; 0/Receptors, Prostaglandin; RXY07S6CZ2/Prostaglandin D2
Comments/Corrections

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