The design of potent and selective inhibitors of DPP-4: Optimization of ADME properties by amide replacements

For a series of β-homophenylalanine based inhibitors of dipeptidyl peptidase IV ADME properties were improved by the incorporation of amide replacements. These efforts led to a novel series of potent and selective inhibitors of DPP-4 that exhibit an attractive pharmacokinetic profile and show excell...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2009-11, Vol.19 (22), p.6340-6345
Hauptverfasser:	Nordhoff, Sonja, Bulat, Stephan, Cerezo-Gálvez, Silvia, Hill, Oliver, Hoffmann-Enger, Barbara, López-Canet, Meritxell, Rosenbaum, Claudia, Rummey, Christian, Thiemann, Meinolf, Matassa, Victor G., Edwards, Paul J., Feurer, Achim
Format:	Artikel
Sprache:	eng
Schlagworte:	Amides - antagonists & inhibitors Amides - chemistry Aminobutyrates - chemistry Biological and medical sciences Caco-2 Cells Cell Line, Tumor Chemistry, Pharmaceutical Diabetes Mellitus, Type 2 - drug therapy Dipeptidyl peptidase IV Dipeptidyl-Peptidase IV Inhibitors - therapeutic use DPP-4 DPP-IV Drug Design General and cellular metabolism. Vitamins GLP-1 Glucagon-like peptide 1 Humans Hypoglycemic Agents - antagonists & inhibitors Hypoglycemic Agents - therapeutic use Medical sciences Pharmacology. Drug treatments Protease Inhibitors - pharmacokinetics Protease Inhibitors - pharmacology Sodium Channels - metabolism Structure-Activity Relationship Type 2 diabetes
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Zusammenfassung:	For a series of β-homophenylalanine based inhibitors of dipeptidyl peptidase IV ADME properties were improved by the incorporation of amide replacements. These efforts led to a novel series of potent and selective inhibitors of DPP-4 that exhibit an attractive pharmacokinetic profile and show excellent efficacy in an animal model of diabetes. For a series of β-homophenylalanine based inhibitors of dipeptidyl peptidase IV ADME properties were improved by the incorporation of amide replacements. These efforts led to a novel series of potent and selective inhibitors of DPP-4 that exhibit an attractive pharmacokinetic profile and show excellent efficacy in an animal model of diabetes.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2009.09.078