Abstract
A novel series of 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives were designed and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4). The phenylalanine series afforded compounds such as 10 that were potent and selective (DPP-4, IC(50)=28nM), but exhibited limited oral bioavailability. The corresponding cyclohexylalanine derivatives such as 25 afforded improved PK exposure and efficacy in a murine OGTT experiment. The X-ray crystal structure of 25 bound to the DPP-4 active site is presented.
MeSH terms
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Administration, Oral
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Alanine / analogs & derivatives*
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Alanine / chemistry
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Alanine / pharmacology
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Animals
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Binding Sites
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Biological Availability
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Crystallography, X-Ray
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Cyclohexanes / chemistry
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Cyclohexanes / pharmacology*
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Dipeptidyl Peptidase 4 / chemistry
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Dipeptidyl-Peptidase IV Inhibitors*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Glucose Tolerance Test
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Mice
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Models, Molecular
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Molecular Structure
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Phenylalanine / analogs & derivatives*
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Phenylalanine / chemistry
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Phenylalanine / pharmacology
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Structure-Activity Relationship
Substances
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4-aminocyclohexylalanine
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Cyclohexanes
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Dipeptidyl-Peptidase IV Inhibitors
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Enzyme Inhibitors
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4-aminophenylalanine
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Phenylalanine
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Dipeptidyl Peptidase 4
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Alanine