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

Authors
  • Van Goethem, Sebastiaan
  • Matheeussen, Veerle
  • Joossens, Jurgen
  • Lambeir, Anne-Marie
  • Chen, Xin
  • De Meester, Ingrid
  • Haemers, Achiel
  • Augustyns, Koen
  • Van der Veken, Pieter
Type
Published Article
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Publication Date
Aug 25, 2011
Volume
54
Issue
16
Pages
5737–5746
Identifiers
DOI: 10.1021/jm200383j
PMID: 21711053
Source
Medline
License
Unknown

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.

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