- Discovery of beta-homophenylalanine based pyrrolidin-2-ylmethyl amides and sulfonamides as highly potent and selective inhibitors of dipeptidyl peptidase IV.
Discovery of beta-homophenylalanine based pyrrolidin-2-ylmethyl amides and sulfonamides as highly potent and selective inhibitors of dipeptidyl peptidase IV.
Bioorganic & medicinal chemistry letters (2009-06-12)
Sonja Nordhoff, Silvia Cerezo-Gálvez, Holger Deppe, Oliver Hill, Meritxell López-Canet, Christian Rummey, Meinolf Thiemann, Victor G Matassa, Paul J Edwards, Achim Feurer
PMID19515557
ABSTRACT
Modifications of DPP-4 inhibitor 5, that was discovered by structure based design, are described and structure-activity relationships discussed. With analogue 7k one of the most potent non-covalent inhibitors of DPP-4 reported to date (IC(50)=0.38nM) was discovered. X-ray structure of inhibitor 7k bound to DPP-4 revealed a hydrogen bonding interaction with Q553. First successful efforts in balancing overall properties, as demonstrated by improved metabolic stability, highlight the potential of this series.