title: Structure-based design of dipeptide derivatives for the human neutral endopeptidase.
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.
authors.affiliation: Biological Science Laboratories, Kao Corporation, 2606 Akabane, Ichikai-machi, Haga-gun, Tochigi 321-3497, Japan. misawa.kensuke@kao.co.jp
authors.forename: Kensuke
authors.initials: K
authors.lastname: Misawa
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yoshimori
authors.forename: Ryoko
authors.initials: R
authors.lastname: Takasawa
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shibuya
authors.forename: Sei-ichi
authors.initials: S
authors.lastname: Tanuma
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008956:Models, Chemical; D008969:Molecular Sequence Data; D015394:Molecular Structure; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; D015260:Neprilysin