Preclinical pharmacology of AZD9977: A novel mineralocorticoid receptor modulator separating organ protection from effects on electrolyte excretion

PloS One
Krister BambergJudith Hartleib-Geschwindner

Abstract

Excess mineralocorticoid receptor (MR) activation promotes target organ dysfunction, vascular injury and fibrosis. MR antagonists like eplerenone are used for treating heart failure, but their use is limited due to the compound class-inherent hyperkalemia risk. 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 eplerenone showed 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 albuminuria and improved kidney histopathology similar to eplerenone in db/db uni-nephrectomised mice and uni-nephrectomised rats. I...Continue Reading

References

May 1, 1971·The Journal of Clinical Investigation·R G SchultzeN S Bricker
Jan 1, 1995·American Journal of Nephrology·A Spital, R H Sterns
Jan 1, 1995·Steroids·R TakedaI A Blair
Aug 1, 1994·Gastroenterology·R AgarwalJ S Fordtran
Oct 24, 1997·Nature·A M BrzozowskiM Carlquist
Mar 30, 2002·Science·Yongfeng Shang, Myles Brown
Jun 6, 2002·Proceedings of the National Academy of Sciences of the United States of America·Zheng LiuBert W O'Malley
Jul 11, 2003·Vitamins and Hormones·David PearceTimothy J Cole
Aug 6, 2004·The New England Journal of Medicine·David N JuurlinkDonald A Redelmeier
Aug 6, 2004·The New England Journal of Medicine·Biff F Palmer
May 24, 2005·Nature Structural & Molecular Biology·Jérôme FagartMarie-Edith Rafestin-Oblin
Jun 11, 2005·Heart Failure Reviews·John W Funder
Jun 22, 2005·The Journal of Biological Chemistry·Randy K BledsoeShawn P Williams
Jun 29, 2005·American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation·Stefano BianchiVito M Campese
Jan 4, 2007·Hypertension·Shigeru ShibataToshiro Fujita
Feb 24, 2007·Current Opinion in Pharmacology·Vera Regitz-ZagrosekCarola Schubert
Jun 16, 2007·Molecular Pharmacology·Jessica HuyetMarie-Edith Rafestin-Oblin
Jul 17, 2007·Molecular and Cellular Endocrinology·Cindy StahnFrank Buttgereit
Jan 25, 2008·Journal of the American Society of Nephrology : JASN·Yufeng HuangNancy A Noble
Nov 20, 2008·Pflügers Archiv : European journal of physiology·Michael Gekle, Claudia Grossmann
Jul 3, 2010·Current Hypertension Reports·Yee LuVito M Campese
Nov 16, 2010·The New England Journal of Medicine·Faiez ZannadUNKNOWN EMPHASIS-HF Study Group
Mar 18, 2011·Kidney International·Jean-Philippe BertocchioFrederic Jaisser
Jul 5, 2011·Molecular and Cellular Endocrinology·Amy McCurley, Iris Z Jaffe
Jul 21, 2011·Molecular and Cellular Endocrinology·Peter Kolkhof, Steffen A Borden
Sep 27, 2012·Journal of Hypertension·GianLuca ColussiLeonardo A Sechi
Nov 23, 2012·Journal of Vascular Research·Marie Briet, Ernesto L Schiffrin
Nov 5, 2013·Journal of the American College of Cardiology·Yoshihiro MatsumotoNobuo Shio

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Citations

Mar 1, 2019·Journal of the Renin-angiotensin-aldosterone System : JRAAS·Krister BambergJudith Hartleib-Geschwindner
Sep 19, 2019·Acta Physiologica·Jonatan Barrera-Chimal, Frederic Jaisser
Mar 5, 2020·Journal of Veterinary Pharmacology and Therapeutics·Sarah SpencerJonathan Elliott
Mar 3, 2020·Current Hypertension Reports·Daisuke SuetaKenichi Tsujita
Nov 13, 2020·Drug Development Research·Vishal PatelMukul Jain
Mar 19, 2021·Hypertension Research : Official Journal of the Japanese Society of Hypertension·Trupti GhatageAudesh Bhat
May 28, 2019·Kidney International·Jonatan Barrera-ChimalFrederic Jaisser
Aug 31, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Peter KolkhofUlrich Kintscher
Nov 23, 2021·The Journal of Organic Chemistry·Lindsey G DeRattScott D Kuduk
Oct 27, 2021·British Journal of Pharmacology·Dorien ClarisseAchim Lother
Nov 18, 2021·British Journal of Pharmacology·Jonatan Barrera-ChimalHans-Joachim Anders
Nov 24, 2021·British Journal of Pharmacology·Ulrich KintscherPeter Kolkhof

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Methods Mentioned

BETA
surface
biosensor
gel filtration
chip
ELISA
X-ray
urine collection

Software Mentioned

GraphPad Prism
XDS
Analyse
Coot
BUSTER
Premier
CCP4
GraphPad
it Excel
Phoenix WinNonlin

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