Details

Autor(en) / Beteiligte

• Kukkola, Paivi J
• Savage, Paula
• Sakane, Yumi
• Berry, J Carol
• Bilci, Natalie A
• Ghai, Rajendra D
• Jeng, Arco Y

Titel

Differential Structure-Activity Relationships of Phosphoramidon Analogues for Inhibition of Three Metalloproteases: Endothelin-Converting Enzyme, Neutral Endopeptidase, and Angiotensin-Converting Enzyme

Ist Teil von

• Journal of cardiovascular pharmacology, 1995, Vol.26 Suppl 3, p.S65-68

Ort / Verlag

United States: Lippincott-Raven Publishers

Erscheinungsjahr

1995

Quelle

MEDLINE

Beschreibungen/Notizen

• The structure-activity relationships of phosphoramidon analogues for inhibition of endothelin-converting enzyme (ECE), neutral endopeptidase 24.11 (NEP), and angiotensin-converting enzyme (ACE) were compared. Phosphoramidon inhibited ECE, NEP, and ACE activities with IC50 values of 3.5, 0.034, and 78 u,M, respectively. Removal of the rhamnose moiety of phosphoramidon (dipeptide 3) reduced the potency for ECE (IC50 = 70 μM), whereas the potencies for NEP (0.003 uJW) and ACE (0.20 μ,M) were increased. Addition of 2-(2-naphthyl)ethyl to dipeptide 3 improved the potency for ECE (0.55 μM) but weakened the potency for NEP (0.02 μ.M), and had no significant change for ACE. Interchange between Leu and Trp abolished the inhibitory activities for ECE and NEP, but the compound remained active for ACE. These results suggest that a hydrophobic group in the P1 position of phosphoramidon analogues increases the potency for ECE significantly, whereas compounds containing a free phosphonic acid are optimal for inhibition of NEP and ACE. Furthermore, an aromatic group in the V2 position is essential for the inhibition of ECE and NEP, but not ACE.