Abstract
Modification of the biphenyl portion of MMP inhibitor 2a gave analogue 2i which is greater than 1000-fold selective against MMP-2 versus MMP-1. The stereospecific synthesis of both enantiomers of 2i was achieved beginning with (S)- or (R)-benzyl glycidyl ether. The (S)-enantiomer, 11 (ABT-770), is orally bioavailable and efficacious in an in vivo model of tumor growth.
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / blood
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacokinetics
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Area Under Curve
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Biological Availability
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Biphenyl Compounds / blood
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Biphenyl Compounds / chemical synthesis
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Biphenyl Compounds / pharmacokinetics*
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Cell Division / drug effects
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Dogs
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Enzyme Inhibitors / blood
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacokinetics
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Half-Life
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Haplorhini
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Hydroxamic Acids / blood
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Hydroxamic Acids / chemical synthesis
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Hydroxamic Acids / pharmacokinetics*
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Inhibitory Concentration 50
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Injections, Intravenous
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Matrix Metalloproteinase Inhibitors*
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Metabolic Clearance Rate
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Neoplasms, Experimental / drug therapy
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Rats
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Biphenyl Compounds
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Enzyme Inhibitors
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Hydroxamic Acids
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Matrix Metalloproteinase Inhibitors
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ABT-770