Abstract
Aprocitentan, a dual endothelin receptor antagonist recently approved for the treatment of resistant hypertension, contains a sulfamide moiety structurally related to known zinc-binding groups found in carbonic anhydrase (CA) inhibitors. Given the central role of CAs in renal and vascular physiology, we investigated whether aprocitentan exerts secondary pharmacological effects via CA inhibition. Kinetic profiling of aprocitentan was performed against all catalytically active human CA isoforms (hCA I-XIV). In addition, X-ray crystallographic structures of aprocitentan in complex with hCA I and hCA II were solved to elucidate the binding mode at the molecular level. These findings highlight a previously unrecognized dual mechanism of action for aprocitentan involving not only endothelin receptor antagonism but also CA inhibition. The combined effect may enhance its antihypertensive efficacy and suggests new avenues for therapeutic exploration in resistant hypertension.