Inhibitors of the enkephalin degrading enzymes Modulation of activity of hydroxamate containing compounds by modifications of the C‐terminal residue

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Abstract
To further characterize the S′2 subsite of both the neutral endopeptidase (EC 3.4.24.11, NEP) and aminopeptidase N (EC 3.4.11.2, APN), two enzymes physiologically involved in enkephalin metabolism, a new series of hydroxamate inhibitors containing a cyclic amino acid as the Pi component were synthesized. These amino acids differ by the size of the cycle, the relative position of the functional groups, and their absolute configuration. Highly efficient inhibitors of NEP were obtained whatever the modification on the Pi component, while for APN inhibition, a cyclic β‐amino acid was preferred. The most active inhibitors contained a trans cyclopentyl β‐amino acid and a Cis or a trans cyclohexyl β‐amino acid. When injected intracerebroventricularly in mice, these two latter compounds elicited potent antinociceptive responses on both the jump latency and the fore paw lick times.

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