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.
Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
Sebastiaan
S
Van Goethem
Pieter
P
Van der Veken
Véronique
V
Dubois
Anna
A
Soroka
Anne-Marie
AM
Lambeir
Xin
X
Chen
Achiel
A
Haemers
Simon
S
Scharpé
Ingrid
I
De Meester
Koen
K
Augustyns
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