Abstract
A series of novel and potent 3,4-diamino-2,5-thiadiazole-1-oxides were prepared and found to show excellent binding affinities for CXCR2 and CXCR1 receptors and excellent inhibitory activity of Gro-alpha and IL-8 mediated in vitro hPMN MPO release of CXCR2 and CXCR1 expressing cell lines. On the other hand, a closely related 3,4-diamino-2,5-thiadiazole-dioxide did not show functional activity despite its excellent binding affinities for CXCR2 and CXCR1 in membrane binding assays. A detailed SAR has been discussed in these two closely related structures.
MeSH terms
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Animals
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Chemokine CXCL1 / chemistry
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Chemokine CXCL1 / pharmacology
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Chemotactic Factors / chemistry
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Chemotactic Factors / pharmacology
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Humans
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Interleukin-8 / chemistry
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Interleukin-8 / pharmacology
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Kinetics
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Neutrophils / drug effects
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Neutrophils / enzymology
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Oxides / chemical synthesis
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Oxides / chemistry
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Oxides / pharmacokinetics
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Oxides / pharmacology
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Peroxidase / metabolism
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Rats
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Receptors, Interleukin-8A / antagonists & inhibitors*
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Receptors, Interleukin-8B / antagonists & inhibitors*
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Structure-Activity Relationship
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Thiadiazoles / chemical synthesis
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Thiadiazoles / chemistry
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Thiadiazoles / pharmacokinetics
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Thiadiazoles / pharmacology
Substances
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Chemokine CXCL1
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Chemotactic Factors
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Interleukin-8
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Oxides
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Receptors, Interleukin-8A
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Receptors, Interleukin-8B
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Thiadiazoles
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Peroxidase