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

PLoS ONE

Volumn 13, Issue 2, 2018, Pages

  Bamberg, Krister ^a   Johansson, Ulrika ^a   Edman, Karl ^a   William Olsson, Lena ^a   Myhre, Susanna ^a   Gunnarsson, Anders ^a   Geschwindner, Stefan ^a   Aagaard, Anna ^a   Granqvist, Anna Björnson ^a   Jaisser, Frédéric ^b   Huang, Yufeng ^c   Granberg, Kenneth L ^a   Jansson Löfmark, Rasmus ^a   Hartleib Geschwindner, Judith ^a  

^a ASTRAZENECA R AND D   (Sweden)

^b CENTRE DE RECHERCHE DES CORDELIERS   (France)

^c UNIVERSITY OF UTAH SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALDOSTERONE; AZD 9977; ENALAPRIL; EPLERENONE; MINERALOCORTICOID ANTAGONIST; MINERALOCORTICOID RECEPTOR; POTASSIUM ION; SODIUM CHLORIDE; SODIUM ION; UNCLASSIFIED DRUG; POTASSIUM; SODIUM; SPIRONOLACTONE;

ALBUMINURIA; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DOSE RESPONSE; DRUG POTENCY; ELECTROLYTE EXCRETION; HEART PROTECTION; HISTOPATHOLOGY; HYPERKALEMIA; IN VITRO STUDY; MOUSE; NEPHRECTOMY; NONHUMAN; RAT; RECEPTOR BINDING; RENAL PROTECTION; RISK REDUCTION; SALT INTAKE; URINARY EXCRETION; X RAY CRYSTALLOGRAPHY; ANALOGS AND DERIVATIVES; ANIMAL; CHEMICAL STRUCTURE; CHEMISTRY; CHRONIC KIDNEY FAILURE; DRUG EFFECT; GENETICS; HUMAN; KIDNEY; MALE; METABOLISM; MUTANT MOUSE STRAIN; ORAL DRUG ADMINISTRATION; PATHOLOGY; PRECLINICAL STUDY; SODIUM INTAKE; SPRAGUE DAWLEY RAT; TUMOR CELL LINE; URINE;

ADMINISTRATION, ORAL; ALDOSTERONE; ANIMALS; CELL LINE, TUMOR; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG EVALUATION, PRECLINICAL; HUMANS; KIDNEY; MALE; MICE, MUTANT STRAINS; MINERALOCORTICOID RECEPTOR ANTAGONISTS; MOLECULAR STRUCTURE; POTASSIUM; RATS, SPRAGUE-DAWLEY; RECEPTORS, MINERALOCORTICOID; RENAL INSUFFICIENCY, CHRONIC; SODIUM; SODIUM, DIETARY; SPIRONOLACTONE;

EID: 85042491659     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0193380     Document Type: Article

References (71)

1. Pearce D, Bhargava A, Cole TJ. Aldosterone: its receptor, target genes, and actions. Vitamins and hormones. 2003; 66: 29–76. PMID: 12852252
2. Lombes M, Alfaidy N, Eugene E, Lessana A, Farman N, Bonvalet JP. Prerequisite for cardiac aldosterone action. Mineralocorticoid receptor and 11 beta-hydroxysteroid dehydrogenase in the human heart. Circulation. 1995; 92(2): 175–182. PMID: 7600648
3. Nishiyama A, Yao L, Fan Y, Kyaw M, Kataoka N, Hashimoto K, et al. Involvement of aldosterone and mineralocorticoid receptors in rat mesangial cell proliferation and deformability. Hypertension. 2005; 45(4): 710–716. https://doi.org/10.1161/01.HYP.0000154681.38944.9a PMID: 15699469
4. Shibata S, Nagase M, Yoshida S, Kawachi H, Fujita T. Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1. Hypertension. 2007; 49(2): 355–364. https://doi.org/10.1161/01.HYP.0000255636.11931.a2 PMID: 17200434
5. Takeda R, Hatakeyama H, Takeda Y, Iki K, Miyamori I, Sheng WP, et al. Aldosterone biosynthesis and action in vascular cells. Steroids. 1995; 60(1): 120–124. PMID: 7792796
6. Gekle M, Grossmann C. Actions of aldosterone in the cardiovascular system: the good, the bad, and the ugly? Pflugers Archiv: Eur J Physiol. 2009; 458(2): 231–246.
7. Ivanes F, Susen S, Mouquet F, Pigny P, Cuilleret F, Sautiere K, et al. Aldosterone, mortality, and acute ischaemic events in coronary artery disease patients outside the setting of acute myocardial infarction or heart failure. Eur Heart J. 2012; 33(2): 191–202. https://doi.org/10.1093/eurheartj/ehr176 PMID: 21719456
8. Jia G, Jia Y, Sowers JR. Role of mineralocorticoid receptor activation in cardiac diastolic dysfunction. Biochim Biophys Acta—Molecular Basis of Disease. 2017; 1863(8): 2012–2018.
9. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999; 341(10): 709–717. https://doi.org/10.1056/NEJM199909023411001PMID: 10471456
10. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011, 364(1): 11–21. https://doi.org/10.1056/NEJMoa1009492 PMID: 21073363
11. Colussi G, Catena C, Sechi LA. Spironolactone, eplerenone and the new aldosterone blockers in endocrine and primary hypertension. Journal Hypertens. 2013; 31(1): 3–15.
12. Bertocchio JP, Warnock DG, Jaisser F. Mineralocorticoid receptor activation and blockade: an emerging paradigm in chronic kidney disease. Kidney Int. 2011; 79(10): 1051–1060. https://doi.org/10.1038/ki.2011.48 PMID: 21412221
13. McCurley A, Jaffe IZ. Mineralocorticoid receptors in vascular function and disease. Mol Cell Endocrinol. 2012; 350(2): 256–265. https://doi.org/10.1016/j.mce.2011.06.014 PMID: 21723914
14. Briet M, Schiffrin EL. Vascular actions of aldosterone. J Vasc Res. 2013; 50(2): 89–99. https://doi.org/10.1159/000345243 PMID: 23172373
15. Blanco-Rivero J, Cachofeiro V, Lahera V, Aras-Lopez R, Marquez-Rodas I, Salaices M, et al. Participation of prostacyclin in endothelial dysfunction induced by aldosterone in normotensive and hypertensive rats. Hypertension. 2005; 46(1): 107–112. https://doi.org/10.1161/01.HYP.0000171479.36880.17PMID: 15956108
16. Nishizaka MK, Zaman MA, Green SA, Renfroe KY, Calhoun DA. Impaired endothelium-dependent flow-mediated vasodilation in hypertensive subjects with hyperaldosteronism. Circulation. 2004; 109 (23): 2857–2861. https://doi.org/10.1161/01.CIR.0000129307.26791.8E PMID: 15173035
17. Lu Y, Ku E, Campese VM. Aldosterone in the pathogenesis of chronic kidney disease and proteinuria. Curr Hypertens Rep. 2010; 12(4): 303–306. https://doi.org/10.1007/s11906-010-0116-4 PMID: 20596805
18. Bianchi S, Bigazzi R, Campese VM. Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int. 2006; 70(12): 2116–2123. https://doi.org/10.1038/sj.ki.5001854 PMID: 17035949
19. Bianchi S, Bigazzi R, Campese VM. Antagonists of aldosterone and proteinuria in patients with CKD: an uncontrolled pilot study. Am J Kidney Dis. 2005; 46(1): 45–51. PMID: 15983956
20. Matsumoto Y, Mori Y, Kageyama S, Arihara K, Sugiyama T, Ohmura H, et al. Spironolactone reduces cardiovascular and cerebrovascular morbidity and mortality in hemodialysis patients. J Am Coll Cardiol. 2014; 63(6): 528–536. https://doi.org/10.1016/j.jacc.2013.09.056 PMID: 24184249
21. White WB, Duprez D, St Hillaire R, Krause S, Roniker B, Kuse-Hamilton J, et al. Effects of the selective aldosterone blocker eplerenone versus the calcium antagonist amlodipine in systolic hypertension. Hypertension. 2003; 41(5): 1021–1026. https://doi.org/10.1161/01.HYP.0000067463.13172.EA PMID: 12682082
22. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. New Eng J Med. 2004; 351(6): 543–551. https://doi.org/10.1056/NEJMoa040135 PMID: 15295047
23. Lazich I, Bakris GL. Prediction and management of hyperkalemia across the spectrum of chronic kidney disease. Sem Nephrol. 2014; 34(3): 333–339.
24. Kojetin DJ, Burris TP. Small molecule modulation of nuclear receptor conformational dynamics: implications for function and drug discovery. Mol Pharmacol. 2013; 83(1): 1–8. https://doi.org/10.1124/mol.112.079285 PMID: 22869589
25. Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature. 1997; 389(6652): 753–758. https://doi.org/10.1038/39645 PMID: 9338790
26. Shang Y, Brown M. Molecular determinants for the tissue specificity of SERMs. Science. 2002; 295 (5564): 2465–2468. https://doi.org/10.1126/science.1068537 PMID: 11923541
27. Kazmin D, Prytkova T, Cook CE, Wolfinger R, Chu TM, Beratan D, et al. Linking ligand-induced alterations in androgen receptor structure to differential gene expression: a first step in the rational design of selective androgen receptor modulators. Mol Endocrinol. 2006; 20(6): 1201–1217. https://doi.org/10.1210/me.2005-0309 PMID: 16574741
28. Liu Z, Auboeuf D, Wong J, Chen JD, Tsai SY, Tsai MJ, et al. Coactivator/corepressor ratios modulate PR-mediated transcription by the selective receptor modulator RU486. Proc Natl Acad Sci U S A. 2002; 99(12): 7940–7944. https://doi.org/10.1073/pnas.122225699 PMID: 12048256
29. Stahn C, Lowenberg M, Hommes DW, Buttgereit F. Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists. Mol Cell Endocrinol. 2007; 275(1–2): 71–78. https://doi.org/10.1016/j.mce.2007.05.019 PMID: 17630118
30. Giannoukos G, Szapary D, Smith CL, Meeker JE, Simons SS Jr. New antiprogestins with partial agonist activity: potential selective progesterone receptor modulators (SPRMs) and probes for receptor- and coregulator-induced changes in progesterone receptor induction properties. Mol Endocrinol. 2001; 15 (2): 255–270. https://doi.org/10.1210/mend.15.2.0596 PMID: 11158332
31. Hultman ML, Krasnoperova NV, Li S, Du S, Xia C, Dietz JD, et al. The ligand-dependent interaction of mineralocorticoid receptor with coactivator and corepressor peptides suggests multiple activation mechanisms. Mol Endocrinol. 2005; 19(6): 1460–1473. https://doi.org/10.1210/me.2004-0537 PMID: 15761029
32. Li Y, Suino K, Daugherty J, Xu HE. Structural and biochemical mechanisms for the specificity of hormone binding and coactivator assembly by mineralocorticoid receptor. Mol Cell. 2005; 19(3): 367–380. https://doi.org/10.1016/j.molcel.2005.06.026 PMID: 16061183
33. Funder JW. Mineralocorticoid receptors: distribution and activation. Heart Fail Rev. 2005; 10(1): 15–22. https://doi.org/10.1007/s10741-005-2344-2 PMID: 15947887
34. Wilson P, Morgan J, Funder JW, Fuller PJ, Young MJ. Mediators of mineralocorticoid receptor-induced profibrotic inflammatory responses in the heart. Clin Sci. 2009; 116(9): 731–739. https://doi.org/10.1042/CS20080247 PMID: 18990085
35. Rossier MF, Lenglet S, Vetterli L, Python M, Maturana A. Corticosteroids and redox potential modulate spontaneous contractions in isolated rat ventricular cardiomyocytes. Hypertension. 2008; 52(4): 721–728. https://doi.org/10.1161/HYPERTENSIONAHA.108.114223 PMID: 18695149
36. Sato A, Funder JW. High glucose stimulates aldosterone-induced hypertrophy via type I mineralocorticoid receptors in neonatal rat cardiomyocytes. Endocrinology. 1996; 137(10): 4145–4153. https://doi.org/10.1210/endo.137.10.8828470 PMID: 8828470
37. Edman K, Hosseini A, Bjursell MK, Aagaard A, Wissler L, Gunnarsson A, et al. Ligand Binding Mechanism in Steroid Receptors: From Conserved Plasticity to Differential Evolutionary Constraints. Structure. 2015; 23(12): 2280–2290. https://doi.org/10.1016/j.str.2015.09.012 PMID: 26602186
38. Kabsch W. Software XDS for image rotation, recognition and crystal symmetry assignment. Acta Crystallogr D. 2010; 66(2): 125–132.
39. Bailey S. The CCP4 suite: programs for protein crystallography. Acta Crystallogr D. 1994; D50(5): 760–763.
40. Bricogne G, Blanc E, Brandl M, Flensburg C, Keller P, Paciorek W, et al. BUSTER. 2009; Global Phasing Limited: Cambridge, United Kingdom.
41. Adams PD, Aertgeerts K, Bauer C, Bell JA, Berman HM, Bhat TN, et al. Outcome of the First wwPDB/ CCDC/D3R Ligand Validation Workshop. Structure. 2016; 24(4): 502–508. https://doi.org/10.1016/j.str.2016.02.017 PMID: 27050687
42. Schrodinger. LLC, The JyMOL Molecular Graphics Development Component, Version 1.8. 2015.
43. Huang Y, Border WA, Yu L, Zhang J, Lawrence DA, Noble NA. A PAI-1 mutant, PAI-1R, slows progression of diabetic nephropathy. J Am Soc Nephrol. 2008; 19(2): 329–338. https://doi.org/10.1681/ASN.2007040510 PMID: 18216319
44. Upton RN, Mould DR. Basic concepts in population modeling, simulation, and model-based drug development: part 3-introduction to pharmacodynamic modeling methods. CPT Pharmacometrics Syst Pharmacol. 2014; 3: e88. https://doi.org/10.1038/psp.2013.71 PMID: 24384783
45. Curtis MJ, Bond RA, Spina D, Ahluwalia A, Alexander SP, Giembycz MA, et al. Experimental design and analysis and their reporting: new guidance for publication in BJP. Br J Pharmacol. 2015; 172(14): 3461–71. https://doi.org/10.1111/bph.12856 PMID: 26114403
46. Bledsoe RK, Madauss KP, Holt JA, Apolito CJ, Lambert MH, Pearce KH, et al. A ligand-mediated hydrogen bond network required for the activation of the mineralocorticoid receptor. J Biol Chem. 2005; 280 (35): 31283–31293. https://doi.org/10.1074/jbc.M504098200 PMID: 15967794
47. Fagart J, Huyet J, Pinon GM, Rochel M, Mayer C, Rafestin-Oblin M-E. Crystal structure of a mutant mineralocorticoid receptor responsible for hypertension. Nature Struct Biol. 2005; 12(6): 554–555.
48. Huyet J, Pinon GM, Fay MR, Fagart J, Rafestin-Oblin ME. Structural basis of spirolactone recognition by the mineralocorticoid receptor. Mol Pharmacol. 2007; 72(3): 563–571. https://doi.org/10.1124/mol.107.036459 PMID: 17569793
49. Carlsson P, Koehler KF, Nilsson L. Glucocorticoid receptor point mutation V571M facilitates coactivator and ligand binding by structural rearrangement and stabilization. Mol Endocrinol. 2005; 19(8): 1960–1977. https://doi.org/10.1210/me.2004-0203 PMID: 15774500
50. Zhou G, Johansson U, Peng XR, Bamberg K, Huang Y. An additive effect of eplerenone to ACE inhibitor on slowing the progression of diabetic nephropathy in the db/db mice. Am J Transl Res. 2016; 8(3): 1339–1354. PMID: 27186263
51. Kolkhof P, Borden SA. Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics. Mol Cell Endocrinol. 2012; 350(2): 310–317. https://doi.org/10.1016/j.mce.2011.06.025PMID: 21771637
52. Gomez-Sanchez EP. Third-generation Mineralocorticoid Receptor Antagonists: Why Do We Need a Fourth? J Cardiovasc Pharmacol. 2016; 67(1): 26–38. https://doi.org/10.1097/FJC.0000000000000329 PMID: 26466326
53. Kolkhof P, Delbeck M, Kretschmer A, Steinke W, Hartmann E, Barfacker L, et al. Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury. J Cardiovasc Pharmacol. 2014; 64(1): 69–78. https://doi.org/10.1097/FJC.0000000000000091 PMID: 24621652
54. Pitt B, Kober L, Ponikowski P, Gheorghiade M, Filippatos G, Krum H, et al. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94–8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur Heart J. 2013; 34(31): 2453–2463. https://doi.org/10.1093/eurheartj/eht187 PMID: 23713082
55. Liu LC, Schutte E, Gansevoort RT, van der Meer P, Voors AA. Finerenone: third-generation mineralocorticoid receptor antagonist for the treatment of heart failure and diabetic kidney disease. Expert Opin Investig Drugs. 2015; 24(8): 1123–1135. https://doi.org/10.1517/13543784.2015.1059819 PMID: 26095025
56. Casimiro-Garcia A, Piotrowski DW, Ambler C, Arhancet GB, Banker ME, Banks T, et al. Identification of (R)-6-(1-(4-cyano-3-methylphenyl)-5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl)-2-me thoxynicotinic acid, a highly potent and selective nonsteroidal mineralocorticoid receptor antagonist. J Med Chem. 2014; 57(10): 4273–4288. https://doi.org/10.1021/jm500206r PMID: 24738581
57. Nariai T, Fujita K, Mori M, Katayama S, Hori S, Matsui K. SM-368229, a novel selective and potent nonsteroidal mineralocorticoid receptor antagonist with strong urinary Na+ excretion activity. J Pharmacol Sci. 2011; 115(3): 346–353. PMID: 21358118
58. Arai K, Tsuruoka H, Homma T. CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, prevents hypertension and cardiorenal injury in Dahl salt-sensitive hypertensive rats. Eur J Pharmacol. 2015; 769: 266–273. https://doi.org/10.1016/j.ejphar.2015.11.028 PMID: 26607463
59. Kagawa CM, Sturtevant FM, Van Arman CG. Pharmacology of a new steroid that blocks salt activity of aldosterone and desoxycorticosterone. J Pharmacol Exp Ther. 1959; 126(2): 123–130. PMID: 13665517
60. Barfacker L, Kuhl A, Hillisch A, Grosser R, Figueroa-Perez S, Heckroth H, et al. Discovery of BAY 94–8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases. Chem Med Chem. 2012; 7(8): 1385–1403. https://doi.org/10.1002/cmdc.201200081 PMID: 22791416
61. Eudy RJ, Sahasrabudhe V, Sweeney K, Tugnait M, King-Ahmad A, Near K, et al. The use of plasma aldosterone and urinary sodium to potassium ratio as translatable quantitative biomarkers of mineralocorticoid receptor antagonism. J Transl Med. 2011; 9: p. 180–190. https://doi.org/10.1186/1479-5876-9-180 PMID: 22017794
62. Eaton Dc PVC, Vander’s Renal Physiology 8th edition. 2013, New York: McGraw/Hill Medical. 284.
63. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. New Engl J Med. 2004; 351(6): 585–592. https://doi.org/10.1056/NEJMra035279 PMID: 15295051
64. Schultze RG, Taggart DD, Shapiro H, Pennell JP, Caglar S, Bricker NS. On the adaptation in potassium excretion associated with nephron reduction in the dog. J Clin Invest. 1971; 50(5): 1061–1068. https://doi.org/10.1172/JCI106577 PMID: 5552407
65. Agarwal R, Afzalpurkar R, Fordtran JS. Pathophysiology of potassium absorption and secretion by the human intestine. Gastroenterology. 1994; 107(2): 548–571. PMID: 8039632
66. Spital A, Sterns RH. Extrarenal potassium adaptation: review of a concept. Am J Nephrol. 1995; 15(5): 367–373. https://doi.org/10.1159/000168868 PMID: 7503134
67. Iqbal J, Parviz Y, Pitt B, Newell-Price J, Al-Mohammad A, Zannad F. Selection of a mineralocorticoid receptor antagonist for patients with hypertension or heart failure. Eur J Heart Fail. 2014; 16(2): 143–150. https://doi.org/10.1111/ejhf.31 PMID: 24464876
68. Weikum ER, Okafor CD, D’Agostino EH, Colucci JK, Ortlund EA, Structural Analysis of the Glucocorticoid Receptor Ligand-Binding Domain in Complex with Triamcinolone Acetonide and a Fragment of the Atypical Coregulator, Small Heterodimer Partner. Mol Pharmacol. 2017; 92(1): 12–21. https://doi.org/10.1124/mol.117.108506 PMID: 28396564
69. Regitz-Zagrosek V, Wintermantel TM, Schubert C. Estrogens and SERMs in coronary heart disease. Curr Opin Pharmacol. 2007; 7(2): 130–139. https://doi.org/10.1016/j.coph.2006.10.009 PMID: 17317318
70. Nielsen FT, Jensen BL, Hansen PB, Marcussen N, Bie P. The mineralocorticoid receptor antagonist eplerenone reduces renal interstitial fibrosis after long-term cyclosporine treatment in rat: antagonizing cyclosporine nephrotoxicity. BMC Nephrol. 2013; 14: 42–49. https://doi.org/10.1186/1471-2369-14-42PMID: 23425330
71. Currie G, Taylor AH, Fujita T, Ohtsu H, Lindhardt M, Rossing P, et al. Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: a systematic review and meta-analysis. BMC Nephrol. 2016; 17(1): 127–140. https://doi.org/10.1186/s12882-016-0337-0PMID: 27609359