Preclinical pharmacology of AZD9977: A novel mineralocorticoid receptor modulator separating organ protection from effects on electrolyte excretion.
2018
Excess
mineralocorticoid receptor(MR) activation promotes target
organ dysfunction, vascular injury and fibrosis. MR antagonists like
eplerenoneare used for treating heart failure, but their use is limited due to the compound class-inherent
hyperkalemiarisk. Here we present evidence that AZD9977, a first-in-class MR modulator shows cardio-renal protection despite a mechanism-based reduced liability to cause
hyperkalemia. AZD9977 in vitro potency and binding mode to MR were characterized using reporter gene, binding, cofactor recruitment assays and X-ray crystallopgraphy. Organ protection was studied in uni-nephrectomised db/db mice and uni-nephrectomised rats administered aldosterone and high salt. Acute effects of single compound doses on urinary electrolyte excretion were tested in rats on a low salt diet. AZD9977 and
eplerenoneshowed similar human MR in vitro potencies. Unlike
eplerenone, AZD9977 is a partial MR antagonist due to its unique interaction pattern with MR, which results in a distinct recruitment of co-factor peptides when compared to
eplerenone. AZD9977 dose dependently reduced
albuminuriaand improved kidney histopathology similar to
eplerenonein db/db uni-nephrectomised mice and uni-nephrectomised rats. In acute testing, AZD9977 did not affect urinary Na+/K+ ratio, while
eplerenoneincreased the Na+/K+ ratio dose dependently. AZD9977 is a selective MR modulator, retaining organ protection without acute effect on urinary electrolyte excretion. This predicts a reduced
hyperkalemiarisk and AZD9977 therefore has the potential to deliver a safe, efficacious treatment to patients prone to
hyperkalemia.
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