Abstract
Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K(i) against DPP4, DPP8, and DPP9 of 0.37 nM, 2.2, and 5.7 μM, respectively, showed a significant improvement in insulin response after single doses of 3 and 10 μmol/kg in ob/ob mice.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Catalytic Domain
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Cytochrome P-450 CYP3A / metabolism*
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Diabetes Mellitus / drug therapy
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Dipeptidyl Peptidase 4 / metabolism*
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Dipeptidyl-Peptidase IV Inhibitors / chemistry*
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Dipeptidyl-Peptidase IV Inhibitors / pharmacokinetics
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Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
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Ether-A-Go-Go Potassium Channels / metabolism*
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Humans
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Insulin / blood
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Insulin / metabolism
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Mice
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Mice, Inbred C57BL
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Models, Molecular
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Pyridines / chemistry*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology*
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Pyrroles / chemistry
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Pyrroles / pharmacokinetics
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Pyrroles / pharmacology
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Rats
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Stereoisomerism
Substances
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Dipeptidyl-Peptidase IV Inhibitors
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Ether-A-Go-Go Potassium Channels
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Insulin
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Pyridines
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Pyrroles
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Cytochrome P-450 CYP3A
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Dipeptidyl Peptidase 4