title: Discovery of beta-homophenylalanine based pyrrolidin-2-ylmethyl amides and sulfonamides as highly potent and selective inhibitors of dipeptidyl peptidase IV.
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.
authors.affiliation: Santhera Pharmaceuticals (Switzerland) Ltd, Hammerstrasse 47, CH-4410 Liestal, Switzerland. sonja.nordhoff@santhera.com
authors.forename: Sonja
authors.initials: S
authors.lastname: Nordhoff
authors.forename: Silvia
authors.initials: S
authors.lastname: Cerezo-Gálvez
authors.forename: Holger
authors.initials: H
authors.lastname: Deppe
authors.forename: Oliver
authors.initials: O
authors.lastname: Hill
authors.forename: Meritxell
authors.initials: M
authors.lastname: López-Canet
authors.forename: Christian
authors.initials: C
authors.lastname: Rummey
authors.forename: Meinolf
authors.initials: M
authors.lastname: Thiemann
authors.forename: Victor G
authors.initials: VG
authors.lastname: Matassa
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Edwards
authors.forename: Achim
authors.initials: A
authors.lastname: Feurer
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000613:Aminobutyrates / Q000737:chemistry*; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D052216:Glucagon-Like Peptide 1 / Q000037:antagonists & inhibitors; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000577:Amides; D000613:Aminobutyrates; D054873:Dipeptidyl-Peptidase IV Inhibitors; D013449:Sulfonamides; C014328:2-amino-4-phenylbutyric acid; D052216:Glucagon-Like Peptide 1