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

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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