Abstract
We previously reported a highly potent DPP-IV inhibitor 6 with low in vivo efficacy. While trying to maintain consistent in vitro and in vivo biological activity, we initiated a pharmacokinetic property-driven optimization to improve the metabolic stability and permeability of inhibitor 6. A simple scaffold replacement of thienopyrimidine with pyrrolopyrimidine (21a) led to significantly improved metabolic stability (4% vs. 65% remaining). Further modification of the pyrrolopyrimidine scaffold to produce compound 21j resulted in much better oral bioavailability than 6. Importantly, compound 21j exhibits greater in vivo efficacy than does 6 and Alogliptin and is worthy of further development.
Copyright © 2012 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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Absorption
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Animals
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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 / metabolism
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Dipeptidyl-Peptidase IV Inhibitors / pharmacokinetics*
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Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
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Drug Design
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Drug Stability
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / metabolism
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Hypoglycemic Agents / pharmacokinetics*
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Hypoglycemic Agents / pharmacology*
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Inhibitory Concentration 50
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Mice
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Pyrimidines / chemistry
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Pyrimidines / metabolism
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Pyrimidines / pharmacokinetics*
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Pyrimidines / pharmacology*
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Pyrroles / chemistry
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Pyrroles / metabolism
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Pyrroles / pharmacokinetics*
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Pyrroles / pharmacology*
Substances
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Dipeptidyl-Peptidase IV Inhibitors
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Hypoglycemic Agents
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Pyrimidines
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Pyrroles
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pyrrolopyrimidine
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Dipeptidyl Peptidase 4