Abstract
From metabolic considerations and prediction of an inhibitor-induced conformational change, novel adenosine deaminase (ADA) inhibitors with improved activities and oral bioavailability have been developed on the basis of our originally designed non-nucleoside ADA inhibitors. They demonstrated in vivo efficacy in models of inflammation and lymphoma. Furthermore, X-ray crystal structure analysis has revealed a novel induced fit to ADA.
MeSH terms
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Adenosine Deaminase / chemistry
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Adenosine Deaminase / metabolism
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Adenosine Deaminase Inhibitors*
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Administration, Oral
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Benzoxazoles / chemical synthesis*
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Benzoxazoles / chemistry
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Benzoxazoles / pharmacology
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Biological Availability
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Crystallography, X-Ray
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Dogs
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Drug Design
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology
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In Vitro Techniques
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Mice
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Mice, SCID
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Microsomes, Liver / metabolism
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Models, Molecular
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Protein Conformation
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Rats
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Structure-Activity Relationship
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U937 Cells
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Xenograft Model Antitumor Assays
Substances
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Adenosine Deaminase Inhibitors
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Anti-Inflammatory Agents, Non-Steroidal
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Antineoplastic Agents
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Benzoxazoles
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Imidazoles
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Adenosine Deaminase