Key result
Nonpeptidic renin inhibitors with P4 4-methoxymethoxypiperidinylamide exhibit slow tight binding driven by the methoxymethoxy moiety.
Why the study?
Some nonpeptidic human renin inhibitors with a 4-methoxymethoxypiperidinylamide at the P4 position exhibit slow tight binding, but the mechanism and structural requirements were unclear.
The 4-methoxymethoxypiperidinylamide group at the P4 position is critical for the slow, tight, non-covalent binding of these nonpeptidic inhibitors to human renin.
Warrants no clinical translation yet; leaves open optimization of nonpeptidic renin inhibitor kinetics.
A series of nonpeptidic human renin inhibitors with a 4-methoxymethoxypiperidinylamide at the P4 position of the molecule exhibited slow tight binding to the enzyme. Replacement of the methoxymethoxy moiety on the piperidine ring with H, OH, methoxyethyl, propyloxy or n-butyl eliminated the effect. The inhibition was partially reversed by prolonged dialysis at 4 degrees C, arguing against formation of a covalent bond in the tightened complex.
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Stein et al. (1992) studied this question. Nonpeptidic human renin inhibitors with a 4-methoxymethoxypiperidinylamide at the P4 position vs. Inhibitors with replacement of the methoxymethoxy moiety (H, OH, methoxyethyl, propyloxy or n-butyl) was evaluated on Binding to human renin enzyme. Nonpeptidic human renin inhibitors with a 4-methoxymethoxypiperidinylamide at the P4 position exhibited slow tight binding to the enzyme, which was eliminated by replacing the methoxymethoxy moiety.
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