Key result
The novel direct renin inhibitor (3S,5R)-12 showed oral bioavailability and demonstrated blood pressure lowering activity in a double-transgenic rat model.
A novel class of oral direct renin inhibitors was discovered, demonstrating oral bioavailability and blood pressure-lowering efficacy in a transgenic rat model.
Advances preclinical oral renin inhibitors; leaves open human efficacy and safety trials.
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.
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Ostermann et al. (2013) studied Hypertension. (3S,5R)-12 (direct renin inhibitor) was evaluated on Blood pressure lowering activity. The novel direct renin inhibitor (3S,5R)-12 showed oral bioavailability and demonstrated blood pressure lowering activity in a double-transgenic rat model.
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