Inhibitors of dipeptidyl peptidase 8 and dipeptidyl peptidase 9. Part 2: isoindoline containing inhibitors.
To obtain selective and potent inhibitors of dipeptidyl peptidases 8 and 9, we synthesized a series of substituted isoindolines as modified analogs of allo-Ile-isoindoline, the reference DPP8/9 inhibitor. The influence of phenyl substituents and different P2 residues on the inhibitors' affinity toward other DPPs and more specifically, their potential to discriminate between DPP8 and DPP9 will be discussed. Within this series compound 8j was shown to be a potent and selective inhibitor of DPP8/9 with low activity toward DPP II.
Van Goethem
Sebastiaan
S
Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
Van der Veken
Pieter
P
Dubois
Véronique
V
Soroka
Anna
A
Lambeir
Anne-Marie
AM
Chen
Xin
X
Haemers
Achiel
A
Scharpé
Simon
S
De Meester
Ingrid
I
Augustyns
Koen
K
D002626:Chemistry, Pharmaceutical / Q000379:methods; D004150:Dipeptidases / Q000037:antagonists & inhibitors*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008239:Lysine / Q000737:chemistry; D008956:Models, Chemical; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007211:Indoles; D009570:Nitriles; D010455:Peptides; D004150:Dipeptidases; C471241:DPP9 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C487997:DPP8 protein, human; D008239:Lysine