Abstract
A series of C32-O-aralkyl ether derivatives of the FK-506 related macrolide ascomycin have been prepared based on an earlier reported C32-O-cinnamyl ether design. In the present study, the nature of the aryl tethering group was varied in an attempt to improve oral activity. An imidazol-2-yl-methyl tether was found to be superior among those investigated and has resulted in an ascomycin analog, L-733,725, with in vivo immunosuppressive activity comparable to FK-506 but with an improved therapeutic index.
MeSH terms
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Animals
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Biological Availability
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Hypothermia / chemically induced
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Imidazoles / chemical synthesis*
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Imidazoles / pharmacology
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Imidazoles / toxicity
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Immunophilins / metabolism
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Immunosuppressive Agents / chemical synthesis*
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Immunosuppressive Agents / pharmacology
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Immunosuppressive Agents / toxicity
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Indicators and Reagents
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Kidney / drug effects
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Kidney / pathology
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Mice
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Mice, Inbred BALB C
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Molecular Conformation
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Molecular Structure
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Neurotoxins / toxicity
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Rats
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Structure-Activity Relationship
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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Tacrolimus / analogs & derivatives*
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Tacrolimus / chemical synthesis*
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Tacrolimus / pharmacology
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Tacrolimus / therapeutic use
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Tacrolimus / toxicity
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Tacrolimus Binding Proteins
Substances
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Imidazoles
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Immunosuppressive Agents
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Indicators and Reagents
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L 733725
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Neurotoxins
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immunomycin
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Tacrolimus Binding Proteins
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Immunophilins
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Tacrolimus