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

Bioorg Med Chem Lett. 2024 Nov 15:113:129940. doi: 10.1016/j.bmcl.2024.129940. Epub 2024 Sep 2.

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.

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Glutamyl Aminopeptidase* / antagonists & inhibitors
  • Glutamyl Aminopeptidase* / metabolism
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protease Inhibitors* / chemical synthesis
  • Protease Inhibitors* / chemistry
  • Protease Inhibitors* / pharmacology
  • Rats
  • Structure-Activity Relationship

Substances

  • Glutamyl Aminopeptidase
  • Protease Inhibitors
  • Enzyme Inhibitors