Abstract
Two novel classes of diphenyloxazole and Ndelta-Z-ornithine derivatives as highly potent and selective EP(4) antagonists have been discovered. The optimized diphenyloxzole 8 and Ndelta-Z-ornithine 11 effectively competed with [(3)H]PGE(2) binding to human recombinant EP(4), with K(i) values of 0.30 nM and 0.91 nM, respectively, and were selective for all members of the human prostanoid receptor family. 8 was shown to exhibit good pharmacokinetic properties in rats and dogs and potent inhibitory activity toward in vitro PGE(2)-promoted IgE synthesis.
MeSH terms
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Adjuvants, Immunologic / chemical synthesis*
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Adjuvants, Immunologic / pharmacokinetics
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Adjuvants, Immunologic / pharmacology
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Animals
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B-Lymphocytes / drug effects
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B-Lymphocytes / metabolism
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Dinoprostone / pharmacology
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Dogs
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Humans
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Immunoglobulin E / biosynthesis
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In Vitro Techniques
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Ornithine / analogs & derivatives*
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Ornithine / chemical synthesis*
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Ornithine / pharmacokinetics
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Ornithine / pharmacology
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Oxazoles / chemical synthesis*
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Oxazoles / pharmacokinetics
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Oxazoles / pharmacology
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Radioligand Assay
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Rats
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Receptors, Prostaglandin E / antagonists & inhibitors*
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Receptors, Prostaglandin E, EP4 Subtype
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Adjuvants, Immunologic
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Oxazoles
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PTGER4 protein, human
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Receptors, Prostaglandin E
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Receptors, Prostaglandin E, EP4 Subtype
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Immunoglobulin E
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Ornithine
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Dinoprostone