Details

Autor(en) / Beteiligte

• Van Goethem, Sebastiaan
• Matheeussen, Veerle
• Joossens, Jurgen
• Lambeir, Anne-Marie
• Chen, Xin
• De Meester, Ingrid
• Haemers, Achiel
• Augustyns, Koen
• Van der Veken, Pieter

Titel

Structure–Activity Relationship Studies on Isoindoline Inhibitors of Dipeptidyl Peptidases 8 and 9 (DPP8, DPP9): Is DPP8-Selectivity an Attainable Goal?

Ist Teil von

• Journal of medicinal chemistry, 2011-08, Vol.54 (16), p.5737-5746

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2011

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.