Irreversible inhibition of dipeptidyl peptidase 8 by dipeptide-derived diaryl phosphonates.
Dipeptide-derived compounds, bearing various P2 residues and a diaryl pyrrolidin-2-yl phosphonate at the P1 position, were evaluated as dipeptidyl peptidase 8 (DPP8) inhibitors. With these products, irreversible inhibition of DPP8 was observed. To obtain inhibitors with an improved activity and selectivity profile, a set of selected analogues containing a diaryl isoindolin-1-ylphosphonate at P1 was synthesized and evaluated. Within this latter series, compound 2e was shown to be a potent, irreversible inhibitor of DPP8, demonstrating very low affinity for DPP IV and DPP II.
Van der Veken
Pieter
P
Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium. pieter.vanderveken@ua.ac.be
Soroka
Anna
A
Brandt
Inger
I
Chen
Yuan-Shou
YS
Maes
Marie-Berthe
MB
Lambeir
Anne-Marie
AM
Chen
Xin
X
Haemers
Achiel
A
Scharpé
Simon
S
Augustyns
Koen
K
De Meester
Ingrid
I
D004150:Dipeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D054833:Isoindoles / Q000138:chemical synthesis* / Q000737:chemistry; D007700:Kinetics; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
D004151:Dipeptides; D054833:Isoindoles; D063065:Organophosphonates; D011759:Pyrrolidines; D004150:Dipeptidases