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A novel class of oral direct renin inhibitors: highly potent 3,5-disubstituted piperidines bearing a tricyclic p3-p1 pharmacophore.

Ostermann N, Ruedisser S, Ehrhardt C, Breitenstein W, Marzinzik A, Jacoby E, Vangrevelinghe E, Ottl J, Klumpp M, Hartwieg JC, Cumin F, Hassiepen U, Trappe J, Sedrani R, Geisse S, Gerhartz B, Richert P, Francotte E, Wagner T, Krömer M, Kosaka T, Webb RL, Rigel DF, Maibaum J, Baeschlin DK
J Med Chem 56 2196-206 (2013)
Related entries: 4gj8, 4gj9, 4gja, 4gjb, 4gjd

Cited: 10 times
EuropePMC logo PMID: 23360239

Abstract

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 P3(sp)-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.

Reviews citing this publication (2)

  1. Twenty years on: the impact of fragments on drug discovery. Erlanson DA, Fesik SW, Hubbard RE, Jahnke W, Jhoti H. Nat Rev Drug Discov 15 605-619 (2016)
  2. Recent progress on the discovery of non-peptidic direct renin inhibitors for the clinical management of hypertension. Yokokawa F. Expert Opin Drug Discov 8 673-690 (2013)

Articles citing this publication (8)



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