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

Abstract

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.

Crystal structure of the mineralocorticoid receptor ligand‐binding domain in complex with a potent and selective nonsteroidal blocker, esaxerenone (CS‐3150)

“…Among several clinical candidates of nonsteroidal MR antagonists , the cocrystal structures of AZD9977 and its derivatives have been reported in detail . According to the reported structures, the binding mode of these compounds well mimics that of steroid compounds such as spironolactone, despite not sharing the same chemical structure as steroids.…”

“…Such a large difference in the binding mode of esaxerenone to MR compared with steroidal antagonists such as spironolactone would never be achieved via conventional structure‐based drug design (SBDD). For example, as reported previously, AZD9977 was meticulously designed from the cocrystal structure of its precursor compounds and spironolactone using the typical SBDD method . Although such an approach works for obtaining highly potent compounds with favorable physicochemical properties, a fundamental difference in the binding mode achieved by esaxerenone was difficult to attain.…”

Advances in the Development of Non-steroidal Mineralocorticoid-receptor Antagonists

“…Interestingly, a carbonyl linker led to AstraZeneca benzoxazinone derivative AZD9977, which is currently in clinical trials (15, Figure 5). In a recent publication, AstraZeneca describes the thorough structure and property studies that led to the identification of this clinical candidate [30]. Additionally, a benzoxazinone derivative with a rather different pattern of substituents was developed by Mitsubishi Tanabe Pharma leading to apararenone (16, Figure 5), which is also in clinical trials .…”

“…However, as expected, derivative 24 is not able to interact with Gln776 or Arg817. On the other hand, the isobutyl substituent of 26 causes a rearrangement resulting in an extension of helix H7 and a reposition of helix H6 [30].…”

“…(A) 2D molecular structures. (B) Superimposition of the X-ray crystal structures of MR LBD bound to compounds 15 (in cyan), 24 (in red), and 25 (in light yellow) on the left and 15 (in cyan), 24 (in red), 25 (in light yellow), and 26 (in purple) on the right[30,50]. The hydrogen bonds and water molecules are depicted as yellow dashed lines and red spheres, respectively.…”