Published in
American Chemical Society, Journal of Medicinal Chemistry, 23(50), p. 5568-5570, 2007
DOI: 10.1021/jm701005a
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Irreversible inhibition of dipeptidyl peptidase 8 by dipeptide-derived diaryl phosphonates
,
Xin Chen,
Achiel Haemers,
Simon Scharpé,
Koen Augustyns,
De Ingrid Meester,
Ingrid De Meester,
P; Soroka A; Brandt I; Chen YS; Maes MB; Lambeir AM; Chen X; Haemers A; Scharpe S; Augustyns K; De Meester I Van der Veken
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- Must obtain written permission from Editor
- Must not violate ACS ethical Guidelines
- Must obtain written permission from Editor
- Must not violate ACS ethical Guidelines
Abstract
Dipeptide-derived compounds, bearing various P2 residues and a diaryl pyrrolidin-2-yl phosphonate at the PI 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.