349401-26-9Relevant academic research and scientific papers
A novel class of oral direct renin inhibitors: Highly potent 3,5-disubstituted piperidines bearing a tricyclic P3 - P1 pharmacophore
Ostermann, Nils,Ruedisser, Simon,Ehrhardt, Claus,Breitenstein, Werner,Marzinzik, Andreas,Jacoby, Edgar,Vangrevelinghe, Eric,Ottl, Johannes,Klumpp, Martin,Hartwieg, J. Constanze D.,Cumin, Frederic,Hassiepen, Ulrich,Trappe, J?rg,Sedrani, Richard,Geisse, Sabine,Gerhartz, Bernd,Richert, Paul,Francotte, Eric,Wagner, Trixie,Kr?mer, Markus,Kosaka, Takatoshi,Webb, Randy L.,Rigel, Dean F.,Maibaum, Jürgen,Baeschlin, Daniel K.
, p. 2196 - 2206 (2013)
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-S 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 P 3sp-tethered tricyclic P3-P1 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.
3 -M0N0- AND 3 , 5-DISUBSTITUTED PIPERIDINE DERIVATIVES AS RENIN INHIBITORS
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Page/Page column 72-73, (2010/11/24)
The invention relates to 3,5-piperidine compounds, these compounds for use in the diagnostic and therapeutic treatment of a warm-blooded animal, especially for the treatment of a disease (= disorder) that depends on activity of renin; the use of a compound of that class for the preparation of a pharmaceutical formulation for the treatment of a disease that depends on activity of renin; the use of a compound of that class in the treatment of a disease that depends on activity of renin; pharmaceutical formulations comprising a 3,5- piperidine compound, and/or a method of treatment comprising administering a 3,5- piperidine compound, a method for the manufacture of a 3,5-piperidine compound, and novel intermediates and partial steps for their synthesis. Especially, the 3,5-piperidine compounds have the formula I, wherein the symbols have the meanings described in the specification.
