Structure-activity relationship studies on isoindoline inhibitors of dipeptidyl peptidases 8 and 9 (DPP8, DPP9): is DPP8-selectivity an attainable goal?

Article Details

Citation

Van Goethem S, Matheeussen V, Joossens J, Lambeir AM, Chen X, De Meester I, Haemers A, Augustyns K, Van der Veken P

Structure-activity relationship studies on isoindoline inhibitors of dipeptidyl peptidases 8 and 9 (DPP8, DPP9): is DPP8-selectivity an attainable goal?

J Med Chem. 2011 Aug 25;54(16):5737-46. doi: 10.1021/jm200383j. Epub 2011 Aug 2.

PubMed ID
21711053 [ View in PubMed
]
Abstract

This work represents the first directed study to identify modification points in the topology of a representative DPP8/9-inhibitor, capable of rendering selectivity for DPP8 over DPP9. The availability of a DPP8-selective compound would be highly instrumental for studying and untwining the biological roles of DPP8 and DPP9 and for the disambiguation of biological effects of nonselective DPP-inhibitors that have mainly been ascribed to blocking of DPPIV's action. The cell-permeable DPP8/9-inhibitor 7 was selected as a lead and dissected into several substructures that were modified separately for evaluating their potential to contribute to selectivity. The obtained results, together with earlier work from our group, clearly narrow down the most probable DPP8-selectivity imparting modification points in DPP8/9 inhibitors to parts of space that are topologically equivalent to the piperazine ring system in 7. This information can be considered of high value for future design of compounds with maximal DPP8 selectivity.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
SaxagliptinDipeptidyl peptidase 4IC 50 (nM)0.6N/AN/ADetails
SitagliptinDipeptidyl peptidase 4IC 50 (nM)40N/AN/ADetails
VildagliptinDipeptidyl peptidase 4IC 50 (nM)120N/AN/ADetails