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Design and development of novel non-peptide agonists at NPR-C

Background

Endothelium-derived C-type natriuretic peptide (CNP) possesses cytoprotective and anti-atherogenic functions that regulate vascular tone and smooth-muscle relaxation and might be key in protecting against ischaemia-reperfusion injury [1]. The finding that many of the vasoprotective effects of CNP are mediated by the natriuretic peptide receptor type-C (NPR-C) suggests that this receptor might represent a novel therapeutic target for the treatment of cardiovascular diseases. Thus, we have designed and developed small molecule drug-like mimetics of CNP agonists at NPRC.

Methods and results

We employ a multi-disciplinary approach that comprises molecular modelling, chemical synthesis and biological and functional assays. The crystal structure of NPR-C was used as the starting point for the design of peptidic and subsequently non-peptidic ligands to the receptor [2]. We have determined which fragments of CNP are crucial for binding to NPR-C and modified the NPR-C antagonist AP-811 using pharmacophore searches to replace the peptide component, which led to the design of a library of compounds that were subsequently synthesised, tested and optimised [3].

Conclusion

Novel and selective non-peptide NPR-C agonists have been identified that relax rat isolated mesenteric arteries in vitro. We foresee that such molecules will facilitate the development of potential therapeutic agents for cardiovascular diseases.

References

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Correspondence to Filipa Mota Quinteiro.

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This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Quinteiro, F.M., Gane, P., Rebstock, AS. et al. Design and development of novel non-peptide agonists at NPR-C. BMC Pharmacol 11 (Suppl 1), P54 (2011). https://doi.org/10.1186/1471-2210-11-S1-P54

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  • DOI: https://doi.org/10.1186/1471-2210-11-S1-P54

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