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

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...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2009-08, Vol.19 (16), p.4818-4823
Hauptverfasser:	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:	Artikel
Sprache:	eng
Schlagworte:	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
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Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2009.06.036