2. Academic Validation
  3. A Series of Substituted Bis-Aminotriazines Are Activators of the Natriuretic Peptide Receptor C

A Series of Substituted Bis-Aminotriazines Are Activators of the Natriuretic Peptide Receptor C

  • J Med Chem. 2022 Apr 14;65(7):5495-5513. doi: 10.1021/acs.jmedchem.1c01974.
Robert J Smith 1,  Cristina Perez-Ternero 2,  Daniel Conole 1,  Capucine Martin 2,  Samuel H Myers 1,  Adrian J Hobbs 2,  David L Selwood 1
Affiliations

Affiliations

  • 1 Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Gower St, London WC1E 6DH, U.K.
  • 2 William Harvey Research Institute, Barts & The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, U.K.
PMID: 35333039 DOI: 10.1021/acs.jmedchem.1c01974
Abstract

C-type natriuretic peptide (CNP) is involved in the regulation of vascular homeostasis, which is at least partly mediated through agonism of natriuretic peptide receptor C (NPR-C), and loss of this signaling has been associated with vascular dysfunction. As such, NPR-C is a novel therapeutic target to treat cardiovascular diseases. A series of novel small molecules have been designed and synthesized, and their structure-activity relationships were evaluated by a surface plasmon resonance binding assay. The biological activity of hit compounds was confirmed through organ bath assays measuring vascular relaxation and inhibition of cAMP production, which was shown to be linked to its NPR-C activity. Lead compound 1 was identified as a potent agonist (EC50 ∼ 1 μM) with promising in vivo pharmacokinetic properties.

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