Synthesis, Biological Evaluation, and Molecular Modeling of 1 -Benzyl-1H-imidazoles as Selective Inhibitors of Aldosterone Synthase (CYP11B2)

Journal of Medicinal Chemistry

Volumn 53, Issue 4, 2010, Pages 1712-1725

  Roumen, Luc ^a   Peeters, Joris W ^b   Emmen, Judith M A ^c   Beugels, Ilona P E ^c   Custers, Erica M G ^d   De Gooyer, Marcel ^d   Plate, Ralf ^d   Pieterse, Koen ^a   Hilbers, Peter A J ^a   Smits, Jos F M ^c   Vekemans, Jef A J ^b   Leysen, Dirk ^c   Ottenheijm, Harry C J ^c   Janssen, Henk M ^b   Rob Hermans, J J ^c  

^a EINDHOVEN UNIVERSITY OF TECHNOLOGY   (Netherlands)

^b SyMO Chem   (Netherlands)

^c MAASTRICHT UNIVERSITY   (Netherlands)

^d MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (3 BROMOBENZYL) 1H IMIDAZOLE; 1 (3 CHLOROBENZYL) 1H IMIDAZOLE; 1 (3 CYANOBENZYL) 1H IMIDAZOLE; 1 (3 FLUOROBENZYL) 1H IMIDAZOLE; 1 (4 AMINOBENZYL) 1H IMIDAZOLE; 1 (4 BROMOBENZYL) 1H IMIDAZOLE; 1 (4 BROMOBENZYL) 5 PHENYL 1H IMIDAZOLE; 1 (4 CHLOROBENZYL) 1H IMIDAZOLE; 1 (4 CHLOROBENZYL) 5 PHENYL 1H IMIDAZOLE; 1 (4 CYANOBENZYL) 1H IMIDAZOLE; 1 (4 CYANOBENZYL) 5 PHENYL 1H IMIDAZOLE; 1 (4 FLUOROBENZYL) 5 PHENYL 1H IMIDAZOLE; 1 BENZYL 1H IMIDAZOLE DERIVATIVE; 1 BENZYL 5 PHENYL 1H IMIDAZOLE; 18 HYDROXYCORTICOSTERONE; 3 (1 BENZYL 1H IMIDAZOL 5 YL) 1 PROPANOL; 3 [1 (4 BROMOBENZYL) 1H IMIDAZOL 5 YL] 1 PROPANOL; 3 [1 (4 CHLOROBENZYL) 1H IMIDAZOL 5 YL] 1 PROPANOL; 3 [1 (4 CYANOBENZYL) 1H IMIDAZOL 5 YL] 1 PROPANOL; 3 [1 (4 FLUOROBENZYL) 1H IMIDAZOL 5 YL] 1 PROPANOL; 3 [1 (4 METHOXYBENZYL) 1H IMIDAZOL 5 YL] 1 PROPANOL; FADROZOLE; IMIDAZOLE DERIVATIVE; METHYL 3 (1 BENZYL 1H IMIDAZOL 5 YL) PROPANOATE; METHYL 3 [1 (4 BROMOBENZYL) 1H IMIDAZOL 5 YL] PROPANOATE; METHYL 3 [1 (4 CHLOROBENZYL) 1H IMIDAZOL 5 YL] PROPANOATE; METHYL 3 [1 (4 CYANOBENZYL) 1H IMIDAZOL 5 YL] PROPANOATE; METHYL 3 [1 (4 FLUOROBENZYL) 1H IMIDAZOL 5 YL] PROPANOATE; METHYL 3 [1 (4 METHOXYBENZYL) 1H IMIDAZOL 5 YL] PROPANOATE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ARTICLE; DRUG SCREENING; DRUG SYNTHESIS; ENZYME INHIBITION; IC 50; IN VITRO STUDY; MOLECULAR DOCKING; MOLECULAR MODEL; PROTEIN INTERACTION;

18-HYDROXYCORTICOSTERONE; ALDOSTERONE SYNTHASE; ANIMALS; BENZYL COMPOUNDS; CATALYTIC DOMAIN; CELL LINE; CRICETINAE; CRICETULUS; FADROZOLE; HUMANS; IMIDAZOLES; MODELS, MOLECULAR; MOLECULAR DYNAMICS SIMULATION; PROTEIN BINDING; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 77649197692     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm901356d     Document Type: Article

References (41)

1. Chai, W.; Danser, A. H. Why are mineralocorticoid receptor antagonists cardioprotective? Naunyn Schmiedeberg's Arch. Pharmacol. 2006, 374 (3), 153-162.
2. Struthers, A. D. Aldosterone: cardiovascular assault. Am. Heart. J. 2002, 144 (5), S2-S7.
3. Weber, M. A. Clinical implications of aldosterone blockade. Am. Heart. J. 2002, 144 (5), S12-S18.
4. Lea, W. B.; Kwak, E. S.; Luther, J. M.; Fowler, S. M.; Wang, Z.; Ma, J.; Fogo, A. B.; Brown, N. J. Aldostereone antagonism or synthase inhibition reduces end-organ damage induced by treatment with angiotensin, and high salt. Kidney Int. 2009, 75 (9), 936-944.
5. Sato, A.; Hayashi, K.; Naruse, M.; Saruta, T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension 2003,41(1), 64-68. (Pubitemid 36056793)
6. Schrier, R.W. Water and sodium retention in edematous disorders: role of vasopressin and aldosterone. Am. J. Med. 2006, 119 (7), S47-S53.
7. Pitt, B.; Williams, G.; Remme, W. J.; Martinez, F.; Lopez-Sendon, J.; Zannad, F.; Neaton, J.; Roniker, B.; Hurley, S.; Burns, D.; Bittman, R.; Kleiman, J. The EPHESUS trial: eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction. Cardiovasc. Drugs. Ther. 2001, 15 (1), 79-87. (Pubitemid 32684565)
8. Pitt, B.; Remme, W.; Zannad, F.; Neaton, J.; Martinez, F.; Roniker, B.; Bittman, R.; Hurley, S.; Kleiman, J.; Gatlin, M. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N. Engl. J. Med. 2003, 348 (14), 1309-1321.
9. Hartmann, R. W.; Muller, U.; Ehmer, P. B. Discovery of selective CYP11B2 (aldosterone synthase) inhibitors for the therapy of congestive heart failure and myocardial fibrosis. Eur. J. Med. Chem. 2003, 38 (4), 363-366.
10. Krum, H.; Nolly, H.; Workman, D; He, W.; Roniker, B.; Krause, S.; Fakouhi, K. Efficacy of eplerenone added to renin-angiotensin blockade in hypertensive patients. Hypertension 2002, 40 (2), 117-123. (Pubitemid 34840085)
11. Sica, D. A. Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis. Heart. Failure. Rev. 2005, 10 (1), 23-29.
12. Rousseau, M. F.; Gurné, O.; Duprez, D.; van Mieghem, W.; Robert, A.; Ahn, S.; Galanti, L.; Ketelslegers, J.-M. Beneficial neurohormonal profile of spironolactone in severe congestive heart failure. J. Am. Coll. Cardiol. 2002, 40 (9), 1596-1601.
13. Fisher, A.; Friel, E. C.; Bernhardt, R.; Gomez-Sanchez, C.; Connell, C.; Fraser, J. M. C.; Davies, E. Effects of 18-hydroxylated steroids on corticoid production by human aldosterone synthase and 11beta-hydroxylase. J. Clin. Encrinol. Metab. 2001, 86 (9), 4326-4329. (Pubitemid 32848554)
14. Okamoto, M.; Nonaka, Y. Molecular biology of rat steroid 11 beta-hydroxylase [P450(11beta)] and aldosterone synthase [P450(11beta, aldo)]. Eur. J. Biochem. 1991, 202 (3), 897-902.
15. Fiebeler, A.; Nussberger, J.; Shagdarsuren, E.; Rong, S.; Hilfenhaus, G.; Al-Saadi. N.; Dechend, R.; Wellner, M.; Meiners, S.; Maser-Gluth, C.;Jeng, A. Y.; Webb, R. L.; Luft, F. C.; Muller, D. N. Aldosterone synthase inhibitor ameliorates angiotensin IIinduced organ, damage. Circulation 2005, 111 (223), 3087-3094.
16. Minnaard-Huiban, M.; Emmen, J. M. A.; Roumen, L.; Beugels, I. P. E.; Cohuet, G. M. S.; van Essen, H.; Ruijters, E.; Pieterse, K.; Hilbers, P. A. J.; Ottenheijm, H. C. J.; Plate, R.; de Gooyer, M. E.; Smits, J. F. M.; Hermans, J. J. R. Fadrozole Reverses Cardiac Fibrosis in Spontaneously Hypertensive Heart Failure Rats: Discordant Enantioselectivity Versus Reduction of Plasma Aldosterone. Endocrinology 2008, 149 (1), 28-31.
17. Huang, B. S.; White, R. A.; Ahmad, M.; Tan, J.; Jeng, A. Y.; Leenen, F. H. Central infusion of aldosterone synthase inhibitor attenuates left ventricular dysfunction and remodeling in rats after myocardial infarction. Cardinvase. Res. 2008, 81 (3), 574-581.
18. Menard, J.; Pascoe, L. Can the dextroenantiomer of the aromatase inhibitor fadrozole be useful for clinical investigation of aldosterone-synthase inhibition? J. Hypertens. 2006, 24 (6), 993-997. (Pubitemid 43772301)
19. Shimoni, Y.; Chen, K.; Emmett, T.; Kargacin, G. Aldosterone and the autocrine modulation of potassium, currents and oxidative stress in the diabetic rat heart. Br. J. Pharmacol. 2008, 154 (3), 675-687.
20. Shiragy, H.; Xue, C. Local renal aldosterone production induces inflammation and matrix formation in kidneys of diabetic rats. Exp. Physiol. 2008, 93 (7), 817-824. (Pubitemid 351904248)
21. Huang, B. S.; White, R. A.; Jeng, A. Y.; Leenen, F. H. Role of central nervous system aldosterone synthase and mineralocorticoid receptors in salt-induced hypertension in Dahl salt-sensitive rats. Am. J. 2009, 296 (4), R994-R1000.
22. Ulmschneider, S.; Müller-Vieira, U; Klein, C. D.; Antes, I.; Lengauer, T.; Hartmann, R. W. Synthesis and evaluation of (pyridylmethylene) tetrahydronaphthalenes/-indanes and structurally modified derivatives: potent and selective inhibitors of aldosterone synthase. J. Med, Chem. 2005, 48 (5), 1563-1575. (Pubitemid 40364563)
23. Voets, M.; Antes, I.; Scherer, C.; Müller-Vieira, U.; Biemel, K.; Barassin, C.; Marchais-Oberwinkler, S.; Hartmann, R. W. Heteroaryl-substituted naphthalenes and structurally modified derivatives: selective inhibitors of CYP11B2 for the treatment of congestive heart failure and myocardial fibrosis. J. Med. Chem. 2005, 48 (21), 6632-6642. (Pubitemid 41504720)
24. Voets, M.; Antes, I.; Scherer, C.; Müller-Vieira, U.; Biemel, K.; Marchais-Oberwinkler, S.; Hartmann, R. W. Synthesis and evaluation of heteroaryl-substituted dihydronaphthalenes and indenes: potent and selective inhibitors of aldosterone synthase (CYPl 1.B2) for the treatment of congestive heart failure and myocardial fibrosis. J. Med, Chem. 2006, 49 (7), 2222-2231.
25. Heim, R.; Lucas, S.; Grombein, C. M.; Ries, C.; Schewe, K. E.; Negri, M.; Muller-Vieira, U.; Birk, B.; Hartmann, R. W. Overcoming Undesirable CYP1A2 Inhibition of Pyridylnaphthalene-Type Aldosterone Synthase Inhibitors: Influence of Heteroaryl Derivatization, on Potency and Selectivity. J. Med. Chem. 2008, 51 (16), 5064-5074.
26. de Graaf, C.; Vermeiden, N. P. E.; Feenstra, K. A. Cytochrome P450 in silico: an integrative modeling approach. J. Med. Chem. 2005, 48 (8), 2725-2755. (Pubitemid 40548088)
27. Lucas, S.; Heim, R.; Negri, M.; Antes, I.; Ries, C.; Schewe, K. E.; Bisi, A.; Gobbi, S.; Hartmann, R. W. Novel aldosterone synthase inhibitors with extended carbocyclic skeleton by a combined ligand-based and structure-based drug design approach. J. Med. Chem. 2008, 51 (19), 6138-6149.
28. Lucas, S.; Heim, R.; Ries, C.; Schewe, K. E.; Birk, B.; Hartmann, R. W. In vivo active aldosterone synthase inhibitors with improved selectivity: lead optimization providing a series of pyridine substituted 3,4-dihydro-1H-quinolin- 2-one derivatives. J. Med. Chem. 2008, 51 (24), 8077-8087.
29. Roumen, L.; Sanders, M. P. A.; Pieterse, K.; Hilbers, P. A. J.; Plate, R.; Custers, E.; de Gooyer, M.; Smits, J. F. M.; Beugels, I.; Enimen, J.; Ottenheijm, H. C. J.; Leysen, D.; Hermans, J. J. R. Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics. J. Comput.- Aided. Mol. Des. 2007, 21 (8), 455-471.
30. Ulmschneider, S.; Müller-Vieira, U.; Mitrenga, M.; Hartmann, R. W.; Oberwinkler-Marchais, S.; Klein, C. D.; Bureik, M.; Bernhardt, R.; Antes, I.; Lengauer, T. Synthesis and evaluation of imidazolylmethylenetetrahydronaphthalenes and imidazolylmethyleneindanes: potent inhibitors of aldosterone synthase. J. Med, Chem. 2005, 48 (6), 1796-1805. (Pubitemid 40396312)
31. Belkina, N. V.; Lisurek, M.; Ivanov, A. S.; Bernhardt, R. Modelling of three-dimensional structures of cytochromes P450 11B1 and 11B2. J. Inorg. Biochem. 2001, 87 (4), 197-207. (Pubitemid 34017224)
32. Dorr, H. G.; Kuhnle, U.; Holthausen, H.; Bidlingmaier, F.; Knorr, D. Etomidate: a selective adrenocortical 11 beta-hydroxylase inhibitor. Klin. Woschenschr. 1984, 62 (21), 1011-1013.
33. 3 receptor. J. Med, Chem. 1996, 39 (6), 1220-1226.
34. Erdmann, B.; Dernier, K.; Gerst, H.; Lenz, D.; Bernhardt, R. Human adrenal CYP11B1: localisation, by in situ hybridization and functional expression in cell cultures. Endocr. Res. 1995, 21 (1-2), 425-435.
35. Denner, K.; Doehmer, J.; Bernhardt, R. Cloning of CYP11B1 and CYP11B2 from normal human adrenal and their functional expression in COS-7 and V79 Chinese hamster cells. Endocr. Res. 1995, 21 (1-2), 443-448.
36. Bottner, B.; Denner, K.; Bernhardt, R. Conferring aldosterone synthesis to human CYP11B1 by replacing key amino acid residues with CYP11B2 ones. Eur J. Biochem. 1998, 252 (3), 458-466.
37. Millet, R.; Domarkas, J.; Houssin, R.; Gilleron, P.; Goossens, J.-F.; Chavatte, P.; Logé, C.; Pommery, N.; Pommery, .J.; Hénichart, J.-P. Potent and selective farnesyl transferase inhibitors. J. Med. Chem. 2004, 47 (27), 6812-6820.
38. MOE (The Molecular Operating Environment) Version 2007.08; Chemical Computing Group Inc.: Sherbrooke Street West, Suite 910, Montreal Canada H3A 2R7. http://chemcomp.com
39. Verdonk, M. L.; Cole, J. C.; Hartshorn, M. J.; Murray, C. W.; Taylor, R. D. Improved protein-ligand docking using GOLD. Proteins 2003, 52 (4), 609-623.
40. Kirton, B.; Murray, C. W.; Verdonk, M. L.; Taylor, R. D. Prediction of binding modes for ligands in the cytochromes P450 and other heme-containing proteins. Proteins: Struct., Funct., Bioinf. 2005, 58 (4), 836-844.
41. Cornish-Bowden, A. Analysis of Enzyme Kinetic Data; Oxford University Press: Oxford, UK, 1995.