Abstract
New dipeptidyl peptidase IV inhibitors were designed based on Alogliptin using a scaffold-hopping strategy. All of the compounds constructed on a thienopyrimidine scaffold demonstrated good inhibition and selectivity for DPP-IV. Compound 10d exhibited subnanomolar (IC(50)=0.33nM) DPP-IV inhibitory activity, good in vivo efficacy and an acceptable pharmacokinetic profile. A pharmacokinetic-driven optimization of 10d may lead to a new class of clinical candidate DPP-IV inhibitors.
Copyright © 2010 Elsevier Masson SAS. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blood Glucose / metabolism
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Diabetes Mellitus, Type 2 / 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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Dipeptidyl-Peptidase IV Inhibitors / therapeutic use
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Dogs
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Drug Discovery
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HEK293 Cells
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Humans
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Male
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Piperidines / chemistry
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Pyrimidines / chemistry*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology*
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Pyrimidines / therapeutic use
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Rats
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Uracil / analogs & derivatives
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Uracil / chemistry
Substances
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Blood Glucose
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Dipeptidyl-Peptidase IV Inhibitors
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Piperidines
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Pyrimidines
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thienopyrimidine
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Uracil
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Dipeptidyl Peptidase 4
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alogliptin