Inhibition of angiotensin-converting enzyme by phosphoramidates and polyphosphates

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Abstract
N.alpha.-Phosphoryl-L-alanyl-L-proline is a reversible competitive inhibitor of angiotensin-converting enzyme [inhibitors of this enzyme have been used as orally active antihypertensives] with a Ki of 1.4 nM. Alkylation of one phosphate oxygen with methyl, ethyl or benzyl does not change the Ki. The high activity of the O-alkylated inhibitors demonstrates that the 2 phosphate oxygen anions do not constitute a bidentate ligand of the active site Zn ion. Substitution of valyltryptophan, glycylglycine or .delta.-aminovaleric acid for alanylproline in the phosphoramidate raises the Ki to 12 nM, 25 .mu.M and 178 .mu.M, respectively. Methylation of the alanine nitrogen in phosphorylalanylproline raises the Ki to 29 .mu.M. Polyphosphates inhibit converting enzyme with the following Ki: phosphate, .apprx. 300 mM; pyrophosphate, 2 mM; tripolyphosphate, 18 .mu.M; tetrapolyphosphate, 150 .mu.M. The inhibition of tripolyphosphate appears to be competitive and is unaffected by the addition of excess Zn ion. Since the Ki of tripolyphosphate is nearly 10-fold lower than that of N-phosphoryl-.delta.-aminovaleric acid and is near that of N.alpha.-phosphorylglycylglycine, its terminal phosphates may bind the Zn site and the cationic site on the enzyme, thus spanning the Si'' and S2'' sites.

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