A selective MR antagonist with carbonic anhydrase inhibitory activity: A strategy for reduction of hyperkalemia risk.

Abstract

Mineralocorticoid receptor (MR) antagonist are a clinically proven drug class for the treatment of hypertension and related heart failure. However, these drugs are prescribed with specific care of hyperkalemia, which has resulted in limited clinical use. We designed novel biphenyl derivatives to have both selective MR antagonistic activity and carbonic anhydrase (CA) inhibitory activity, and then found that our biphenyl derivatives show anti-hypertensive activity with lower hyperkalemia risk. Further improvement in pharmacokinetic properties of these derivatives led to the compound that showed remarkable in vivo efficacy in the animal models of hypertension with lower hyperkalemia risk than spironolactone.