Discovery and evaluation of a novel monocyclic series of CXCR2 antagonists

[Display omitted] Antagonism of the chemokine receptor CXCR2 has been proposed as a strategy for the treatment of inflammatory diseases such as arthritis, chronic obstructive pulmonary disease and asthma. Earlier series of bicyclic CXCR2 antagonists discovered at AstraZeneca were shown to have low s...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2015-04, Vol.25 (7), p.1616-1620
Main Authors: Austin, Rupert P., Bennion, Colin, Bonnert, Roger V., Cheema, Lal, Cook, Anthony R., Cox, Rhona J., Ebden, Mark R., Gaw, Alasdair, Grime, Ken, Meghani, Premji, Nicholls, David, Phillips, Caroline, Smith, Neal, Steele, John, Stonehouse, Jeffrey P.
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Amides - chemistry
Amides - pharmacology
Animals
Biological Availability
Chemokine antagonism
CXCR2
Dose-Response Relationship, Drug
Drug Discovery
Humans
Inflammatory disease
Molecular Conformation
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Rats
Receptors, Interleukin-8B - antagonists & inhibitors
Solubility
Structure-Activity Relationship
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Summary:[Display omitted] Antagonism of the chemokine receptor CXCR2 has been proposed as a strategy for the treatment of inflammatory diseases such as arthritis, chronic obstructive pulmonary disease and asthma. Earlier series of bicyclic CXCR2 antagonists discovered at AstraZeneca were shown to have low solubility and poor oral bioavailability. In this Letter we describe the design, synthesis and characterisation of a new series of monocyclic CXCR2 antagonists with improved solubility and good pharmacokinetic profiles.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2015.01.067