2. Academic Validation
  3. Rational design, synthesis and pharmacological characterization of novel aminopeptidase A inhibitors

Rational design, synthesis and pharmacological characterization of novel aminopeptidase A inhibitors

  • Bioorg Med Chem Lett. 2024 Sep 2:113:129940. doi: 10.1016/j.bmcl.2024.129940.
Fabrice Balavoine 1,  Delphine Compere 2,  Frédéric Miege 3,  Nadia De Mota 4,  Mathilde Keck 2,  Mickael Fer 3,  Aude Christen 3,  Emmeline Martin 3,  Didier Roche 3,  Catherine Llorens-Cortes 5,  Vincent Rodeschini 6
Affiliations

Affiliations

  • 1 Quantum Genomics, 6 rue Cambacérès, F-75008 Paris, France. Electronic address: fabrice.balavoine@gmail.com.
  • 2 Quantum Genomics, 6 rue Cambacérès, F-75008 Paris, France; Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Collège de France, Center for Interdisciplinary Research in Biology (CIRB), INSERM U1050/CNRS UMR7241, 11 place Marcelin Berthelot, F-75005 Paris, France.
  • 3 Edelris, Bâtiment Bioserra 1 60 av Rockefeller, F-69003 Lyon, France.
  • 4 Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Collège de France, Center for Interdisciplinary Research in Biology (CIRB), INSERM U1050/CNRS UMR7241, 11 place Marcelin Berthelot, F-75005 Paris, France.
  • 5 Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Collège de France, Center for Interdisciplinary Research in Biology (CIRB), INSERM U1050/CNRS UMR7241, 11 place Marcelin Berthelot, F-75005 Paris, France. Electronic address: c.llorens-cortes@college-de-france.fr.
  • 6 Edelris, Bâtiment Bioserra 1 60 av Rockefeller, F-69003 Lyon, France. Electronic address: vincent.rodeschini@edelris.com.
PMID: 39233188 DOI: 10.1016/j.bmcl.2024.129940
Abstract

Aminopeptidase A (APA) is a membrane-bound zinc metallopeptidase involved in the production of angiotensin III, one effector peptide of the brain renin-angiotensin system, making brain APA a relevant pharmacological target for the development of novel therapeutic treatments against hypertension and heart failure. The structure-based design of new APA inhibitors is described, based on previously developed thiol-containing inhibitors and APA crystal structure. Chemical synthesis, in vitro assessment against APA activity, pharmacological and pharmacokinetic profiling were performed, ultimately leading to a potent and selective APA inhibitor.

Keywords

Aminopeptidase A; Aminophosphinic acid; Metalloprotease inhibitor; Renin-angiotensin system; Structure-activity relationships.

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