Journal of Medicinal Chemistry p. 2196 - 2206 (2013)
Update date:2022-08-15
Topics:
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.
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.
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