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Bioorg Med Chem Lett. 2011 Dec 15;21(24):7399-404. doi: 10.1016/j.bmcl.2011.10.013. Epub 2011 Oct 19.

Renin inhibitors for the treatment of hypertension: design and optimization of a novel series of spirocyclic piperidines.

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Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Québec, Canada H9H 3L1.


The discovery and SAR of a novel series of spirocyclic renin inhibitors are described herein. It was found that by restricting the northern aromatic plate to the bioactive conformation through spirocyclization, increase in renin potency and decrease in hERG affinity could both be realized. When early members of this series were found to be potent time-dependent CYP3A4 inhibitors, two distinct strategies to address this liability were explored and this effort culminated in the identification of compound 31 as an optimized renin inhibitor.

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