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

• Published in: Bioorganic & medicinal chemistry letters 2009-11, Vol.19 (22), p.6340-6345
• Main Authors: 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: Article
• Language: English
• Subjects: 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
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.09.078

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.