title: Irreversible inhibition of dipeptidyl peptidase 8 by dipeptide-derived diaryl phosphonates.
abstract: 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.
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium. pieter.vanderveken@ua.ac.be
authors.forename: Pieter
authors.initials: P
authors.lastname: Van der Veken
authors.forename: Anna
authors.initials: A
authors.lastname: Soroka
authors.forename: Inger
authors.initials: I
authors.lastname: Brandt
authors.forename: Yuan-Shou
authors.initials: YS
authors.lastname: Chen
authors.forename: Marie-Berthe
authors.initials: MB
authors.lastname: Maes
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lambeir
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Achiel
authors.initials: A
authors.lastname: Haemers
authors.forename: Simon
authors.initials: S
authors.lastname: Scharpé
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
authors.forename: Ingrid
authors.initials: I
authors.lastname: De Meester
mesh_terms: 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
chemical_list: D004151:Dipeptides; D054833:Isoindoles; D063065:Organophosphonates; D011759:Pyrrolidines; D004150:Dipeptidases