Bis-aryloxadiazoles as effective activators of the aryl hydrocarbon receptor

Bis-aryloxadiazoles are common scaffolds in medicinal chemistry due to their wide range of biological activities. Previously, we identified a 1,2,4-bis-aryloxadiazole that blocks mammary branching morphogenesis through activation of the aryl hydrocarbon receptor (AHR). In addition to defects in mamm...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2014-06, Vol.24 (11), p.2473-2476
Main Authors: Basham, Kaitlin J., Bhonde, Vasudev R., Kieffer, Collin, Mack, James B.C., Hess, Matthew, Welm, Bryan E., Looper, Ryan E.
Format: Article
Language:English
Subjects:
Aryl hydrocarbon receptor
Branching morphogenesis
Dioxin
Dose-Response Relationship, Drug
Humans
Mammary gland
Models, Molecular
Molecular Structure
Oxadiazole
Oxadiazoles - chemical synthesis
Oxadiazoles - chemistry
Oxadiazoles - pharmacology
Receptors, Aryl Hydrocarbon - metabolism
Structure-Activity Relationship
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Summary:Bis-aryloxadiazoles are common scaffolds in medicinal chemistry due to their wide range of biological activities. Previously, we identified a 1,2,4-bis-aryloxadiazole that blocks mammary branching morphogenesis through activation of the aryl hydrocarbon receptor (AHR). In addition to defects in mammary differentiation, AHR stimulation induces toxicity in many other tissues. We performed a structure activity relationship (SAR) study of 1,2,4-bis-aryloxadiazole to determine which moieties of the molecule are critical for AHR activation. We validated our results with a functional biological assay, using desmosome formation during mammary morphogenesis to indicate AHR activity. These findings will aid the design of oxadiazole derivative therapeutics with reduced off-target toxicity profiles.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2014.04.013