Discovery of beta-homophenylalanine based pyrrolidin-2-ylmethyl amides and sulfonamides as highly potent and selective inhibitors of dipeptidyl peptidase IV.
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Nordhoff S, Cerezo-Galvez S, Deppe H, Hill O, Lopez-Canet M, Rummey C, Thiemann M, Matassa VG, Edwards PJ, Feurer A
Discovery of beta-homophenylalanine based pyrrolidin-2-ylmethyl amides and sulfonamides as highly potent and selective inhibitors of dipeptidyl peptidase IV.
Bioorg Med Chem Lett. 2009 Aug 1;19(15):4201-3. doi: 10.1016/j.bmcl.2009.05.109. Epub 2009 May 30.
- PubMed ID
- 19515557 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) N-({(2S)-1-[(3R)-3-AMINO-4-(2-FLUOROPHENYL)BUTANOYL]PYRROLIDIN-2-YL}METHYL)BENZAMIDE Dipeptidyl peptidase 4 IC 50 (nM) 90 N/A N/A Details N-({(2S)-1-[(3R)-3-amino-4-(3-chlorophenyl)butanoyl]pyrrolidin-2-yl}methyl)-3-(methylsulfonyl)benzamide Dipeptidyl peptidase 4 IC 50 (nM) 0.38 N/A N/A Details