title: Structure-activity relationship studies on isoindoline inhibitors of dipeptidyl peptidases 8 and 9 (DPP8, DPP9): is DPP8-selectivity an attainable goal?
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.
authors.affiliation: Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp (UA), Universiteitsplein 1, B-2610 Wilrijk, Antwerp, Belgium.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Van Goethem
authors.forename: Veerle
authors.initials: V
authors.lastname: Matheeussen
authors.forename: Jurgen
authors.initials: J
authors.lastname: Joossens
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lambeir
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Ingrid
authors.initials: I
authors.lastname: De Meester
authors.forename: Achiel
authors.initials: A
authors.lastname: Haemers
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
authors.forename: Pieter
authors.initials: P
authors.lastname: Van der Veken
mesh_terms: D000595:Amino Acid Sequence; D004150:Dipeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D054833:Isoindoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D008956:Models, Chemical; D015394:Molecular Structure; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D054833:Isoindoles; D004150:Dipeptidases; C471241:DPP9 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C487997:DPP8 protein, human