Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection.
2019
The mechanism-based risk for
hyperkalemiahas limited the use of
mineralocorticoid receptorantagonists (
MRAs) like
eplerenonein 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
MRAsbut still demonstrated equally efficacious organ protection as
eplerenoneafter 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+ ra...
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