Inhibitors of dipeptidyl peptidase 8 and dipeptidyl peptidase 9. Part 1: identification of dipeptide derived leads.
Dipeptide derivatives bearing various P2 residues and pyrrolidine derivatives as P1 mimics were evaluated in order to identify lead structures for the development of DPP8 and DPP9 inhibitors. Structure-activity-relationship data obtained in this way led to the preparation of a series of alpha-aminoacyl ((2S, 4S)-4-azido-2-cyanopyrrolidines). These compounds were shown to be nanomolar DPP8/9 inhibitors with modest overall selectivity toward DPP IV and DPP II.
Department of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium. pieter.vanderveken@ua.ac.be
Pieter
P
Van der Veken
Ingrid
I
De Meester
Véronique
V
Dubois
Anna
A
Soroka
Sebastiaan
S
Van Goethem
Marie-Berthe
MB
Maes
Inger
I
Brandt
Anne-Marie
AM
Lambeir
Xin
X
Chen
Achiel
A
Haemers
Simon
S
Scharpé
Koen
K
Augustyns
D002626:Chemistry, Pharmaceutical / Q000379:methods; D004150:Dipeptidases / Q000037:antagonists & inhibitors*; D004151:Dipeptides / Q000737:chemistry; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008239:Lysine; D008956:Models, Chemical; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011759:Pyrrolidines / Q000737:chemistry; D013329:Structure-Activity Relationship
D004151:Dipeptides; D004791:Enzyme Inhibitors; D009570:Nitriles; D010455:Peptides; D011759:Pyrrolidines; D004150:Dipeptidases; C471241:DPP9 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C487997:DPP8 protein, human; D008239:Lysine