A Novel Class of Oral Direct Renin Inhibitors: Highly Potent 3,5-Disubstituted Piperidines Bearing a Tricyclic P3鈥?/b>P1 Pharmacophore

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• 作者：Nils Ostermann ; Simon Ruedisser ; Claus Ehrhardt ; Werner Breitenstein ; Andreas Marzinzik ; Edgar Jacoby ; Eric Vangrevelinghe ; Johannes Ottl ; Martin Klumpp ; J. Constanze D. Hartwieg ; Frederic Cumin ; Ulrich Hassiepen ; J枚rg Trappe ; Richard Sedrani ; Sabine Geisse ; Bernd Gerhartz ; Paul Richert ; Eric Francotte ; Trixie Wagner ; Markus Kr枚mer ; Takatoshi Kosaka ; Randy L. Webb ; Dean F. Rigel ; J眉rgen Maibaum ; Daniel K. Baeschlin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 28, 2013
• 年：2013
• 卷：56
• 期：6
• 页码：2196-2206
• 全文大小：383K
• 年卷期：v.56,no.6(March 28, 2013)
• ISSN：1520-4804

文摘

A small library of fragments comprising putative recognition motifs for the catalytic dyad of aspartic proteases was generated by in silico similarity searches within the corporate compound deck based on rh-renin active site docking and scoring filters. Subsequent screening by NMR identified the low-affinity hits 3 and 4 as competitive active site binders, which could be shown by X-ray crystallography to bind to the hydrophobic S₃鈥揝₁ pocket of rh-renin. As part of a parallel multiple hit-finding approach, the 3,5-disubstituted piperidine (rac)-5 was discovered by HTS using a enzymatic assay. X-ray crystallography demonstrated the eutomer (3S,5R)-5 to be a peptidomimetic inhibitor binding to a nonsubstrate topography of the rh-renin prime site. The design of the potent and selective (3S,5R)-12 bearing a P₃^sp-tethered tricyclic P₃鈥揚₁ pharmacophore derived from 3 is described. (3S,5R)-12 showed oral bioavailability in rats and demonstrated blood pressure lowering activity in the double-transgenic rat model.