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A Novel Class of Oral Direct Renin Inhibitors: Highly Potent 3,5-Disubstituted Piperidines Bearing a Tricyclic P 3 – P 1 Pharmacophore

2013; American Chemical Society; Volume: 56; Issue: 6 Linguagem: Inglês

10.1021/jm301706j

1520-4804

Nils Ostermann, Simon Ruedisser, Claus Ehrhardt, Werner Breitenstein, Andreas L. Marzinzik, Edgar Jacoby, Eric Vangrevelinghe, Johannes Ottl, Martin Klumpp, J. Constanze D. Hartwieg, Frédéric Cumin, Ulrich Hassiepen, Jörg Trappe, Richard Sedrani, Sabine Geisse, Bernd Gerhartz, Paul Richert, Eric Francotte, Trixie Wagner, Markus Krömer, Takatoshi Kosaka, Randy L. Webb, Dean F. Rigel, Jürgen Maibaum, Daniel K. Baeschlin,

Renin-Angiotensin System Studies

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–S1 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 P3sp-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.