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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Granberg KL,Yuan ZQ,Lindmark B,Edman K,Kajanus J,Hogner A,Malmgren M,O'Mahony G,Nordqvist A,Lindberg J,Tångefjord S,Kossenjans M,Löfberg C,Brånalt J,Liu D,Selmi N,Nikitidis G,Nordberg P,Hayen A,Aagaard A,Hansson E

doi

10.1021/acs.jmedchem.8b01523

subject

Has Abstract

pub_date

2019-02-14 00:00:00

pages

1385-1406

issue

3

eissn

0022-2623

issn

1520-4804

journal_volume

62

pub_type

杂志文章

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