Small-molecule inhibitor: phosphoramidon

Summary Literature

Name

Common name
phosphoramidon
Other names
N-phenethylphosphonyl-L-leucyl-L-tryptophane; NPLT

Inhibition

History
Phosphoramidon was first described by Suda et al. (1973).
Peptidases inhibited
Metallopeptidases inhibited are in families M4 and M13. Ki values (nM) are 3 (neprilysin), 28 (thermolysin), 250 (pseudolysin) (Salvesen & Nagase, 2001). IC50 values reported for endothelin-converting enzyme-1 range from 14 nM to 8 micromolar, because phosphoramidon is a much more potent inhibitor of this enzyme at acidic pH (Ahn et al., 1998). Generally does not inhibit peptidases in other families. Angiotensin-converting enzyme compound peptidase is weakly inhibited (Kukkola et al., 1995).
Mechanism
Inhibition is reversible. Structures of complexes of phosphoramidon with thermolysin, bacillolysin), neprilysin and endothelin-converting enzyme-1 have been determined or predicted (Weaver et al., 1977; Tronrud et al., 1986; Tsuru et al., 1993; Oefner et al., 2000; Bur et al., 2001).
DrugBank
DB02557

Chemistry

CID at PubChem
439265
ChEBI
345067
Structure
[phosphoramidon (M04.001 inhibitor) structure ]
Chemical/biochemical name
rhamnosyl-PO2-Leu-Trp
Formula weight
544
Related inhibitors
Phosphoryl-Leu-Trp

Properties

Synthesis
De Nanteuil et al. (1995)
Stability
Stable at acid or neutral pH for at least 6 days at 37° C (<%Poncz %etal, 1984[20040511J824]%>).

General

Inhibitor class
This compound is of the class of phosphorous-containing inhibitors of metallopeptidases. Such compounds commonly act as transition-state analogues (Bartlett & Marlowe, 1983). Reviewed by Powers & Harper (1986), pp. 237-244.
Comment
Removal of the rhamnose moiety of phosphoramidon reduced the potency for endothelin-converting enzyme-1, but increased that against neprilysin and angiotensin-converting enzyme (Kukkola et al., 1995). The rhamnosyl group may stabilise the compound against spontaneous hydrolysis (Poncz et al., 1984).