Abstract
Following the discovery of N-acyl-1,4-diazepan-2-one as a novel pharmacophore for potent and selective DPP-4 inhibitors, optimization of this new lead with different substitution on the seven-membered ring resulted in several highly potent and selective, orally bioavailable, and efficacious DPP-4 inhibitors, such as 3R-methyl-1-cyclopropyl-1,4-diazepan-2-one derivative 9i (DPP-4 IC(50)=8.0 nM) and 3R,6R-dimethyl-1,4-diazepan-2-one derivative 14a (DPP-4 IC(50)=9.7 nM).
MeSH terms
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Administration, Oral
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Animals
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Azepines / chemical synthesis*
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Azepines / pharmacology
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Chemistry, Pharmaceutical / methods*
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Diabetes Mellitus, Type 2 / drug therapy*
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Dipeptidyl-Peptidase IV Inhibitors*
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology*
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Inhibitory Concentration 50
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Male
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Mice
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Models, Chemical
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Molecular Conformation
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Rats
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Rats, Sprague-Dawley
Substances
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1,4-diazepan-2-one
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Azepines
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Dipeptidyl-Peptidase IV Inhibitors
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Enzyme Inhibitors