Rapid parallel synthesis of dipeptide diphenyl phosphonate esters as inhibitors of dipeptidyl peptidases.
In this paper, we present a parallel synthesis of several series of dipeptide diphenyl phosphonates that are known to be irreversible inhibitors of serine proteases. Polymer-assisted solution-phase synthesis (PASP) is used for the rapid and clean coupling between various alpha-aminoalkyl diphenyl phosphonate ester building blocks and commercially available or easily accessible amino acids. These compounds were used for the rapid profiling of dipeptidyl peptidase II (DPP II) and the closely related dipeptidyl peptidase IV (DPP IV). A highly selective DPP II inhibitor was identified, N-cyclopentylglycyl-NHCH(C(6)H(5))PO(OPh)(2) (9.35), that will be useful to discriminate between DPP II and DPP IV in biological systems in order to further elucidate the biological function of DPP II.
Department of Medicinal Chemistry and Department of Medical Biochemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
Kristel
K
Senten
Liesbeth
L
Daniëls
Pieter
P
Van der Veken
Ingrid
I
De Meester
Anne-Marie
AM
Lambeir
Simon
S
Scharpé
Achiel
A
Haemers
Koen
K
Augustyns
D000409:Alanine / Q000138:chemical synthesis / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004952:Esters / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005998:Glycine / Q000138:chemical synthesis / Q000737:chemistry; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011392:Proline / Q000138:chemical synthesis / Q000737:chemistry
D004791:Enzyme Inhibitors; D004952:Esters; D011392:Proline; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D000409:Alanine; D005998:Glycine