Structure-based design of dipeptide derivatives for the human neutral endopeptidase.

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Misawa K, Suzuki Y, Takahashi S, Yoshimori A, Takasawa R, Shibuya Y, Tanuma S

Structure-based design of dipeptide derivatives for the human neutral endopeptidase.

Bioorg Med Chem. 2011 Oct 15;19(20):5935-47. doi: 10.1016/j.bmc.2011.08.064. Epub 2011 Sep 1.

PubMed ID

21937235 [ View in PubMed

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Abstract

Neutral endopeptidase (NEP) plays a key role in the metabolic inactivation of various bioactive peptides such as atrial natriuretic peptide (ANP), endothelins, and enkephalins. Furthermore, NEP is known to work as elastase in skin fibroblast. Therefore, effective inhibitors of NEP offer significant therapeutic interest as antihypertensives, analgesics, and skin anti-aging agents. Recently, the X-ray crystal structure of human NEP complexed with phosphoramidon has been reported and provided insights into the active site specificity of NEP. Here, we designed new inhibitors by using in silico molecular modeling and synthesized them by short steps. Expectedly, we found highly effective inhibitors with sub-nanomolar levels of IC(50) values. These results indicate that our structure-based molecular designing program is useful for obtaining novel NEP inhibitors. Furthermore, these inhibitors may be attractive leads for the generation of new pharmaceuticals for NEP-related diseases.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Phosphoramidon	Neprilysin	IC 50 (nM)	2	N/A	N/A	Details