From lead to preclinical candidate: Optimization of β-homophenylalanine based inhibitors of dipeptidyl peptidase IV

• Published in: Bioorganic & medicinal chemistry letters 2009-08, Vol.19 (16), p.4818-4823
• Main Authors: Nordhoff, Sonja, López-Canet, Meritxell, Hoffmann-Enger, Barbara, Bulat, Stephan, Cerezo-Gálvez, Silvia, Hill, Oliver, Rosenbaum, Claudia, Rummey, Christian, Thiemann, Meinolf, Matassa, Victor G., Edwards, Paul J., Feurer, Achim
• Format: Article
• Language: English
• Subjects: Administration, Oral; Aminobutyrates - chemical synthesis; Aminobutyrates - chemistry; Aminobutyrates - pharmacokinetics; Animals; Biological and medical sciences; Caco-2 Cells; Cell Line, Tumor; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl peptidase IV; Dipeptidyl-Peptidase IV Inhibitors; Dogs; DPP-4; DPP-IV; General and cellular metabolism. Vitamins; GLP-1; Glucagon-like peptide 1; Humans; Hydrocarbons, Fluorinated - chemical synthesis; Hydrocarbons, Fluorinated - chemistry; Hydrocarbons, Fluorinated - pharmacology; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacokinetics; Medical sciences; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacokinetics; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolidines - pharmacology; Rats; Structure-Activity Relationship; Type 2 diabetes
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.06.036

A series of highly potent and selective inhibitors of DPP-4 was optimized for ADMET properties. The effort resulted in the discovery of inhibitor 1g, that exhibits excellent efficacy in an oral glucose tolerance test and an attractive pharmacokinetic profile. A series of highly potent and selective inhibitors of DPP-4 was optimized for ADMET properties. The effort resulted in the discovery of inhibitor 1g, that exhibits excellent efficacy in an oral glucose tolerance test and an attractive pharmacokinetic profile.