Abstract
An extensive structure-activity relationship (SAR) study of 72 dipeptidyl boronic acid proteasome inhibitors constructed from β-amino acids is reported. SAR analysis revealed that bicyclic groups at the R¹ position, 3-F substituents at the R² position, and bulky aliphatic groups at the R³ position were favorable to the activities. Enzymatic screening results showed that compound 78, comprising all of these features, was the most active inhibitor against the 20S human proteasome at less than a 2 nM level, as active as the marketed drug bortezomib. Cellular assays confirmed that compound 78 was the most potent against two hematologic and some solid tumor cells with IC₅₀ values less than 1 μM. Pharmacokinetic profiles suggested that 78 showed higher plasma exposure and a longer half-life than bortezomib.
MeSH terms
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Amino Acids / chemical synthesis*
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Amino Acids / pharmacokinetics
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Amino Acids / pharmacology
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Boronic Acids / chemical synthesis*
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Boronic Acids / pharmacokinetics
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Boronic Acids / pharmacology
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Bortezomib
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Cell Line, Tumor
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Dipeptides / chemical synthesis*
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Dipeptides / pharmacokinetics
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Dipeptides / pharmacology
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Drug Screening Assays, Antitumor
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Humans
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Male
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Proteasome Inhibitors*
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Pyrazines / pharmacokinetics
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Pyrazines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Stereoisomerism
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Structure-Activity Relationship
Substances
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1-(3-(3-fluorophenyl)-3-(1,2,3,4-tetrahydronaphthalene-4-carboxamido)propanamido)-3-methylbutyl boronic acid
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Amino Acids
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Antineoplastic Agents
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Boronic Acids
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Dipeptides
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Proteasome Inhibitors
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Pyrazines
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Bortezomib