Structure‐Based Design, Synthesis, and in vitro Evaluation of Nonpeptidic Neprilysin Inhibitors

Neprilysin (NEP, neutral endopeptidase, EC 3.4.24.11) is a mammalian zinc(ii)-dependent, membrane-bound endopeptidase. NEP is widely distributed in the organs, particularly in the kidneys and lungs, and is involved in the metabolism of a number of smaller regulatory peptides of the nervous, cardiovascular, inflammatory, and immune systems. Enkephalins are among its natural substrates, and blocking NEP would increase their level, thereby generating an analgetic response. Furthermore, NEP cleaves ANP (atrial natriuretic peptide) and bradykinin, which both reduce blood pressure, and NEP inhibitors could therefore be possible antihypertensive agents. On the other hand, NEP has recently been shown to cleave amyloid b-peptide, the deposition of which in the brain is part of the initiation of Alzheimer's disease. These therapeutic and basic pharmacological research interests led us to develop new nonpeptidic inhibitors of Neprilysin by X-ray structurebased de novo design. Many peptidic NEP inhibitors are known, but only a few nonpeptidic ones have been report-

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