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
  • 1. Quantum Genomics, 6 rue Cambacérès, F-75008 Paris, France. Electronic address: [email protected].
  • 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: [email protected].
  • 6. Edelris, Bâtiment Bioserra 1 60 av Rockefeller, F-69003 Lyon, France. Electronic address: [email protected].
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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