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.
Van der Veken
Pieter
P
Department of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium. pieter.vanderveken@ua.ac.be
De Meester
Ingrid
I
Dubois
Véronique
V
Soroka
Anna
A
Van Goethem
Sebastiaan
S
Maes
Marie-Berthe
MB
Brandt
Inger
I
Lambeir
Anne-Marie
AM
Chen
Xin
X
Haemers
Achiel
A
Scharpé
Simon
S
Augustyns
Koen
K
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