Inhibition of angiotensin converting enzyme by 2-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2-azabicyclo [3.3.0]octane-3-carboxylic acid (Hoe 498 diacid). Comparison with captopril and enalaprilat.

The interaction of angiotensin converting enzyme (ACE) with 2-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyl]-(1S,3S,5S) - 2 - azabicyclo[3.3.0]octane - 3 - carboxylic acid (Hoe 498 diacid) and its ester 2-[N-[(S)-1-ethoxycarbonyl-3 - phenylpropyl] - L - alanyl]-(1S,3S,5S)- 2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) was studied at pH 7.5 in the presence of 300 mmol/l sodium chloride with furanacryloyl-Phe-Gly-Gly as substrate. Hoe 498 diacid inhibits ACE with a Ki value of 7 pmol/l. It is both a slow-and tight-binding inhibitor; the mode of inhibition is fully competitive. Binding of Hoe 498 diacid to ACE proceeds by a two-step mechanism E+I in equilibrium EI in equilibrium EI* in which the inhibitor rapidly binds to enzyme to form an initial enzyme-inhibitor complex which then undergoes a slow isomerization. The interaction of Hoe 498 diacid with ACE is compared to that of the two other potent inhibitors, captopril and enalaprilat.