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Unveiling the Carbonic Anhydrase Inhibitory Profile of Aprocitentan: Kinetic and Structural Characterization.
Andrea Angeli1, Marta Ferraroni2, Claudiu T Supuran1
1NEUROFARBA Department, Sezione di Scienze Farmaceutiche, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
ACS Medicinal Chemistry Letters
|August 20, 2025
Summary
Aprocitentan, used for resistant hypertension, also inhibits carbonic anhydrase (CA), an enzyme crucial for blood pressure regulation. This dual action may improve its effectiveness in treating hypertension.
Area of Science:
- Biochemistry
- Pharmacology
- Medicinal Chemistry
Background:
- Aprocitentan is a dual endothelin receptor antagonist approved for resistant hypertension.
- Its structure contains a sulfamide moiety, similar to zinc-binding groups in carbonic anhydrase (CA) inhibitors.
- Carbonic anhydrases play key roles in renal and vascular physiology.
Purpose of the Study:
- To investigate if aprocitentan exhibits secondary pharmacological effects through carbonic anhydrase inhibition.
- To characterize the interaction of aprocitentan with human carbonic anhydrase isoforms.
Main Methods:
- Kinetic profiling of aprocitentan against all catalytically active human CA isoforms (hCA I-XIV).
- X-ray crystallography to determine the binding mode of aprocitentan with hCA I and hCA II.
Main Results:
- Aprocitentan demonstrated inhibitory activity against human carbonic anhydrase isoforms.
- X-ray structures revealed the molecular basis of aprocitentan binding to hCA I and hCA II.
- This indicates a previously unrecognized dual mechanism of action for aprocitentan.
Conclusions:
- Aprocitentan possesses a dual mechanism of action, inhibiting both endothelin receptors and carbonic anhydrases.
- This combined effect might enhance its antihypertensive efficacy.
- Suggests potential new therapeutic strategies for resistant hypertension involving CA inhibition.
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