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

Abstract

BackgroundEndothelium-derived C-type natriuretic peptide (CNP)possesses cytoprotective and anti-atherogenic functionsthat regulate vascular tone and smooth-muscle relaxa-tion and might be key in protecting against ischaemia-reperfusion injury [1]. The finding that many of thevasoprotective effects of CNP are mediated by thenatriuretic peptide receptor type-C (NPR-C) suggeststhat this receptor might represent a novel therapeutictarget for the treatment of cardiovascular diseases. Thus,we have designed and developed small molecule drug-like mimetics of CNP agonists at NPRC.Methods and resultsWe employ a multi-disciplinary approach that comprisesmolecular modelling, chemical synthesis and biologicaland functional assays. The crystal structure of NPR-Cwas used as the starting point for the design of peptidicand subsequently non-peptidic ligands to the receptor[2]. We have determined which fragments of CNP arecrucial for binding to NPR-C and modified the NPR-Cantagonist AP-811 using pharmacophore searches toreplace the peptide component, which led to the designof a library of compounds that were subsequentlysynthesised, tested and optimised [3].ConclusionNovel and selective non-peptide NPR-C agonists havebeen identified that relax rat isolated mesenteric arteriesin vitro. We foresee that such molecules will facilitatethe development of potential therapeutic agents for car-diovascular diseases.