Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases

Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2013-11, Vol.21 (21), p.6582-6591
Main Authors: Sandham, David A., Arnold, Nicola, Aschauer, Heinrich, Bala, Kamlesh, Barker, Lucy, Brown, Lyndon, Brown, Zarin, Budd, David, Cox, Brian, Docx, Cerys, Dubois, Gerald, Duggan, Nicholas, England, Karen, Everatt, Brian, Furegati, Marcus, Hall, Edward, Kalthoff, Frank, King, Anna, Leblanc, Catherine J., Manini, Jodie, Meingassner, Josef, Profit, Rachael, Schmidt, Alfred, Simmons, Jennifer, Sohal, Bindi, Stringer, Rowan, Thomas, Matthew, Turner, Katharine L., Walker, Christoph, Watson, Simon J., Westwick, John, Willis, Jennifer, Williams, Gareth, Wilson, Caroline
Format: Article
Language:English
Subjects:
Administration, Oral
Allergy
Animals
antagonists
bioavailability
chemistry
chemotypes
CHO Cells
Cricetinae
Cricetulus
CRTh2 receptor antagonist
Dermatitis, Contact - drug therapy
disease models
Disease Models, Animal
Drug Evaluation, Preclinical
Eosinophils - drug effects
Eosinophils - metabolism
Half-Life
Humans
Hypersensitivity - drug therapy
Indolizines - chemistry
Indolizines - pharmacokinetics
Indolizines - therapeutic use
lymphocyte proliferation
Mice
Mice, Inbred BALB C
Protein Binding
Rats
Rats, Sprague-Dawley
Receptors, Immunologic - antagonists & inhibitors
Receptors, Immunologic - genetics
Receptors, Immunologic - metabolism
Receptors, Prostaglandin - antagonists & inhibitors
Receptors, Prostaglandin - genetics
Receptors, Prostaglandin - metabolism
screening
Structure-Activity Relationship
Th2 Cells - immunology
Th2 Cells - metabolism
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Summary:Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2013.08.025