Title
Structure-activity relationship studies on isoindoline inhibitors of dipeptidyl peptidases 8 and 9 (DPP8, DPP9) : is DPP8-selectivity an attainable goal? Structure-activity relationship studies on isoindoline inhibitors of dipeptidyl peptidases 8 and 9 (DPP8, DPP9) : is DPP8-selectivity an attainable goal?
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
Washington, D.C. ,
Subject
Chemistry
Pharmacology. Therapy
Source (journal)
Journal of medicinal chemistry. - Washington, D.C., 1963, currens
Volume/pages
54(2011) :36 , p. 5737-5746
ISSN
0022-2623
ISI
000294077300009
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
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 DPPIVs 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.
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