Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection

The mechanism-based risk for hyperkalemia
has limited the use of
mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal
diseases. Here, we describe the structure and property-driven lead
generation and optimization, which resulted in identification of MR
modulators (S)-1 and (S)-33. Both compounds were partial MRAs but still demonstrated
equally efficacious organ protection as eplerenone after 4 weeks of
treatment in uni-nephrectomized rats on high-salt diet and aldosterone
infusion. Importantly, and in sharp contrast to eplerenone, this was
achieved without substantial changes to the urine Na+/K+ ratio after acute treatment in rat, which predicts a reduced
risk for hyperkalemia. This work led to selection of (S)-1 (AZD9977) as the clinical candidate
for treating MR-mediated cardio-renal diseases, including chronic
kidney disease and heart failure. On the basis of our findings, we
propose an empirical model for prediction of compounds with low risk
of affecting the urinary Na+/K+ ratio in vivo.