Abstract
2-Aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel bicyclic pyrazolone core, are described. Many showed low-nanomolar activity against lipopolysaccharide-induced TNF-alpha production in monocytic cells. Secondary screening data are presented for the pyrimidinyl bicyclic pyrazolones. Several of these analogues showed good oral bioavailability in rat and efficacy in the rat iodoacetate in vivo model.
MeSH terms
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Administration, Oral
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Animals
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Biological Availability
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Humans
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In Vitro Techniques
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Monocytes / drug effects
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Monocytes / metabolism
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Phosphotransferases / antagonists & inhibitors
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Phosphotransferases / metabolism
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Rats
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / antagonists & inhibitors*
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Tumor Necrosis Factor-alpha / biosynthesis
Substances
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Pyrazoles
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Pyrimidines
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Tumor Necrosis Factor-alpha
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Phosphotransferases