The mineralocorticoid receptor (MR) is a receptor with the same affinity for mineralocorticoid and glucocorticoid. Besides, it belongs to the nuclear receptor family, which interacts with receptors and leads to signal transduction that affects the expression of specific genes in the nucleus. Moreover, MR is a regulator of blood pressure and can regulate renal sodium treatment in response to its main ligand aldosterone. Extrarenal MR plays a relevant role in controlling cardiovascular and metabolic functions. Furthermore, MR activation promotes vasoconstriction and acts as an effective fibrogenic agent in cardiovascular remodeling.
Specifically, MR integrates hormone signals and activates the expression of aldosterone target genes, so as to control various physiological processes. Meanwhile, MR plays an important role not only in regulating sodium and water homeostasis but also in cardiovascular function, neuronal fate, and adipocyte differentiation. Nonetheless, the imbalance of MR aldosterone system reveals its importance in various human diseases. Here, we will introduce a selective, and orally active MR modulator, AZD9977.
AZD9977 is a Selective and Orally Active Mineralocorticoid Receptor (MR) Modulator.
Above all, AZD9977 is used for heart failure and chronic kidney disease research. Interestingly, AZD9977 actives MR, GR, PR, and AR with pKi values of MR, GR, and PR are 7.5, 5.4, and 4.6, respectively.
Next in importance, AZD9977 antagonizes aldosterone-activated MR with an IC50 of 0.28 μM in U2-OS cells. Whereas eplerenone is a full antagonist, AZD9977 suppresses only 69% of the MR activity in this assay. Importantly, species selective potencies of AZD9977 are established in reporter gene assays using the MR LBDs from humans, mice, or rats. Particularly, the corresponding IC50 values are 0.37 μM, 0.08 μM and 0.08μM, respectively.
Once again, AZD9977 dose-dependently reduces the UACR in uni-nephrectomized male Sprague Dawley rats administered aldosterone and fed a high-salt diet. Obviously, AZD9977 is as efficacious as full MR antagonists on renal protection, despite the partial antagonism observed in in vitro assays. Additionally, AZD9977 stops further disease progression and reduces urine albumin excretion (UAE) compared to vehicle treatment.
All in all, AZD9977 is a potent, selective, and orally active mineralocorticoid receptor (MR) modulator.
Fredrik Erlandsson, et al. Br J Clin Pharmacol. 2018 Jul;84(7):1486-1493.