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

• Published in: Bioorganic & medicinal chemistry letters Vol. 113; p. 129940
• Main Authors: Balavoine, Fabrice, Compere, Delphine, Miege, Frédéric, De Mota, Nadia, Keck, Mathilde, Fer, Mickael, Christen, Aude, Martin, Emmeline, Roche, Didier, Llorens-Cortes, Catherine, Rodeschini, Vincent
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-11-2024
• Subjects: Aminopeptidase A; Aminophosphinic acid; Metalloprotease inhibitor; Renin-angiotensin system; Structure-activity relationships; Aminopeptidase A; Aminophosphinic acid; Metalloprotease inhibitor; Renin-angiotensin system; Structure-activity relationships
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2024.129940

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•The structure-based design of novel α-aminophosphinic derivatives inhibiting APA is described.•Their chemical synthesis is presented, including an enantioselective route.•QGC583 displays an IC50 of 4 nM on APA and a high selectivity towards APN.•Physico-chemical, ADME and pharmacokinetic parameters are presented.•QGC583 inhibits brain, renal and cardiac APA activities after intravenous administration in rats.
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.