Fine-tuning the selectivity of aldosterone synthase inhibitors: Structure-activity and structure-selectivity insights from studies of heteroaryl substituted 1,2,5,6-tetrahydropyrrolo[3,2,1- ij ]quinolin-4-one derivatives

Journal of Medicinal Chemistry

Volumn 54, Issue 7, 2011, Pages 2307-2319

  Lucas, Simon ^a   Negri, Matthias ^a   Heim, Ralf ^a   Zimmer, Christina ^a   Hartmann, Rolf W ^a,b  

^a SAARLAND UNIVERSITY   (Germany)

^b SAARLAND UNIVERSITY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

1,2,5,6 TETRAHYDROPYRROLO[3,2,1 IJ]QUINOLIN 4 ONE DERIVATIVE; ALDOSTERONE SYNTHASE; CYTOCHROME P450 INHIBITOR; PYRROLOQUINOLINONE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DRUG POTENCY; DRUG SCREENING; DRUG SELECTIVITY; DRUG STRUCTURE; MOLECULAR MODEL; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ALDOSTERONE SYNTHASE; ANIMALS; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; MALE; MODELS, MOLECULAR; PROTEIN CONFORMATION; QUINOLINES; RATS; RATS, WISTAR; STRUCTURE-ACTIVITY RELATIONSHIP; SUBSTRATE SPECIFICITY;

EID: 79953772535     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm101470k     Document Type: Article

References (75)

1. Weber, K. T. Aldosterone in congestive heart failure N. Engl. J. Med. 2001, 345, 1689-1697 (Pubitemid 33126826)
2. Brilla, C. G. Renin-angiotensin-aldosterone system and myocardial fibrosis Cardiovasc. Res. 2000, 47, 1-3
3. Lijnen, P.; Petrov, V. Induction of cardiac fibrosis by aldosterone J. Mol. Cell. Cardiol. 2000, 32, 865-879 (Pubitemid 30663097)
4. Struthers, A. D. Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in chronic heart failure J. Card. Failure 1996, 2, 47-54 (Pubitemid 126666354)
5. Sato, A.; Saruta, T. Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in essential hypertensive patients with left ventricular hypertrophy J. Int. Med. Res. 2001, 29, 13-21 (Pubitemid 32236891)
6. Pitt, B.; Zannad, F.; Remme, W. J.; Cody, R.; Castaigne, A.; Perez, A.; Palensky, J.; Wittes, J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure N. Engl. J. Med. 1999, 341, 709-717 (Pubitemid 29407370)
7. 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, 1309-1321 (Pubitemid 36384098)
8. Hu, X.; Bolten, C. W. Adrenal corticosteroids, their receptors and hypertension Drug Dev. Res. 2006, 67, 871-883 (Pubitemid 46606736)
9. Hu, X.; Li, S.; McMahon, E. G.; Lala, D. S.; Rudolph, A. E. Molecular mechanisms of mineralocorticoid receptor antagonism by eplerenone Mini. Rev. Med. Chem. 2005, 5, 709-718 (Pubitemid 41051894)
10. Juurlink, D. N.; Mamdani, M. M.; Lee, D. S.; Kopp, A.; Austin, P. C.; Laupacis, A.; Redelmeier, D. A. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study N. Engl. J. Med. 2004, 351, 543-551 (Pubitemid 39025171)
11. Delcayre, C.; Swynghedauw, B. Molecular mechanisms of myocardial remodeling. The role of aldosterone J. Mol. Cell. Cardiol. 2002, 34, 1577-1584 (Pubitemid 36001997)
12. Wehling, M. Specific, nongenomic actions of steroid hormones Annu. Rev. Physiol. 1997, 59, 365-393 (Pubitemid 27142447)
13. Lösel, R.; Wehling, M. Nongenomic actions of steroid hormones Nature Rev. Mol. Cell. Biol. 2003, 4, 46-55
14. Hartmann, R. W. Selective inhibition of steroidogenic P450 enzymes: current status and future perspectives Eur. J. Pharm. Sci. 1994, 2, 15-16 (Pubitemid 24292106)
15. Ehmer, P. B.; Bureik, M.; Bernhardt, R.; MSller, U.; Hartmann, R. W. Development of a test system for inhibitors of human aldosterone synthase (CYP11B2): Screening in fission yeast and evaluation of selectivity in V79 cells J. Steroid Biochem. Mol. Biol. 2002, 81, 173-179 (Pubitemid 34876409)
16. Hartmann, R. W.; Batzl, C. Aromatase inhibitors. Synthesis and evaluation of mammary tumor inhibiting activity of 3-alkylated 3-(4-aminophenyl) piperidine-2,6-diones J. Med. Chem. 1986, 29, 1362-1369 (Pubitemid 16034622)
17. Le Borgne, M.; Marchand, P.; Duflos, M.; Delevoye-Seiller, B.; Piessard-Robert, S.; Le Baut, G.; Hartmann, R. W.; Palzer, M. Synthesis and in vitro evaluation of 3-(1-azolylmethyl)-1 H -indoles and 3-(1-azolyl-1- phenylmethyl)-1 H -indoles as inhibitors of P450 arom Arch. Pharm. (Weinheim, Germany) 1997, 330, 141-145 (Pubitemid 27298759)
18. Hille, U. E.; Hu, Q.; Vock, C.; Negri, M.; Bartels, M.; Mgller-Vieira, U.; Lauterbach, T.; Hartmann, R. W. Novel CYP17 inhibitors: synthesis, biological evaluation, structure-activity relationships and modelling of methoxy- and hydroxy-substituted methyleneimidazolyl biphenyls Eur. J. Med. Chem. 2009, 44, 2765-2775
19. Hu, Q.; Yin, L.; Jagusch, C.; Hille, U. E.; Hartmann, R. W. Isopropylidene substitution increases activity and selectivity of biphenylmethylene 4-pyridine type CYP17 inhibitors J. Med. Chem. 2010, 53, 5049-5053
20. Kawamoto, T.; Mitsuuchi, Y.; Toda, K.; Yokoyama, Y.; Miyahara, K.; Miura, S.; Ohnishi, T.; Ichikawa, Y.; Nakao, K.; Imura, H.; Ulick, S.; Shizuta, Y. Role of steroid 11-hydroxylase and steroid 18-hydroxylase in the biosynthesis of glucocorticoids and mineralocorticoids in humans Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 1458-1462
21. 123I]Iodometomidate for Molecular Imaging of Adrenocortical Cytochrome P450 Family 11B Enzymes J. Clin. Endocrinol. Metab. 2008, 93, 2358-65 (Pubitemid 351831559)
22. Zolle, I. M.; Berger, M. L.; Hammerschmidt, F.; Hahner, S.; Schirbel, A.; Peric-Simov, B. New selective inhibitors of steroid 11-hydroxylation in the adrenal cortex. Synthesis and structure-activity relationship of potent etomidate analogues J. Med. Chem. 2008, 51, 2244-2253 (Pubitemid 351503279)
23. Bassett, M. H.; Mayhew, B.; Rehman, K.; White, P. C.; Mantero, F.; Arnaldi, G.; Stewart, P. M.; Bujalska, I.; Rainey, W. E. Expression profiles for steroidogenic enzymes in adrenocortical disease J. Clin. Endocrinol. Metab. 2005, 90, 5446-5455 (Pubitemid 41262314)
24. Taymans, S. E.; Pack, S.; Pak, E.; Torpy, D. J.; Zhuang, Z.; Stratakis, C. A. Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3 J. Clin. Endocrinol. Metab. 1998, 83, 1033-1036 (Pubitemid 28496489)
25. Ulmschneider, S.; MEller-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, 1796-1805 (Pubitemid 40396312)
26. Ulmschneider, S.; Mcller-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, 1563-1575 (Pubitemid 40364563)
27. Voets, M.; Antes, I.; Scherer, C.; M ller-Vieira, U.; Biemel, K.; Barassin, C.; Oberwinkler-Marchais, 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, 6632-6642 (Pubitemid 41504720)
28. 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, 6138-6149
29. Voets, M.; Antes, I.; Scherer, C.; MÜller-Vieira, U.; Biemel, K.; Oberwinkler-Marchais, S.; Hartmann, R. W. Synthesis and evaluation of heteroaryl-substituted dihydronaphthalenes and indenes: Potent and selective inhibitors of aldosterone synthase (CYP11B2) for the treatment of congestive heart failure and myocardial fibrosis J. Med. Chem. 2006, 49, 2222-2231
30. 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, 197-207 (Pubitemid 34017224)
31. Lewis, D. F. V.; Lee-Robichaud, P. Molecular modelling of steroidogenic cytochromes P450 from families CYP11, CYP17, CYP19 and CYP21 based on the CYP102 crystal structure J. Steroid Biochem. Mol. Biol. 1998, 66, 217-233 (Pubitemid 28401696)
32. Krone, N.; Riepe, F. G.; Götze, D.; Korsch, E.; Rister, M.; Commentz, J.; Partsch, C.-J.; Grötzinger, J.; Peter, M.; Sippell, W. G. Congenital adrenal hyperplasia due to 11-hydroxylase deficiency: functional characterization of two novel point mutations and a three-base pair deletion in the CYP11B1 gene J. Clin. Endocrinol. Metab. 2005, 90, 3724-3730 (Pubitemid 41014348)
33. Roumen, L. L.; Sanders, M. P. A.; Koen, P.; Hilbers, P. A. J.; Plate, R.; Custers, E.; de Gooyer, M.; Smits, J. F. M.; Beugels, I.; Emmen, 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, 455-471 (Pubitemid 47423278)
34. Ulmschneider, S.; Negri, M.; Voets, M.; Hartmann, R. W. Development and evaluation of a pharmacophore model for inhibitors of aldosterone synthase (CYP11B2) Bioorg. Med. Chem. Lett. 2006, 16, 25-30 (Pubitemid 41625634)
35. Crabb, T. A.; Soilleux, S. L. Microbiological transformations. Part 9: Microbiological transformations of 1,2,5,6-tetrahydropyrrolo[3,2,1- i,j ]-quinolin-4-one and of derivatives of 1,2,3,5,6,7-hexahydropyrido[3,2,1- i,j ]quinoline with the fungus Cunninghamella elegans Tetrahedron 1986, 42, 5407-5413
36. Appukkuttan, P.; Orts, A. B.; Chandran, R., P.; Goeman, J. L.; van der Eycken, J.; Dehaen, W.; van der Eycken, E. Generation of a small library of highly electron-rich 2-(hetero)aryl-substituted phenethylamines by the Suzuki-Miyaura reaction: a short synthesis of an apogalanthamine analogue Eur. J. Org. Chem. 2004, 3277-3285
37. Zhu, H.-F.; Zhao, W.; Okamura, T.; Fan, J.; Sun, W.-Y.; Ueyama, N. Syntheses and crystal structures of 1D tubular chains and 2D polycatenanes built from the asymmetric 1-(1-imidazolyl)-4-(imidazol-1-ylmethyl)benzene ligand with metal salts New J. Chem. 2004, 28, 1010-1018 (Pubitemid 39280188)
38. Ishiyama, T.; Murata, M.; Miyaura, N. Palladium(0)-catalyzed cross-coupling reaction of alkoxydiboron with haloarenes: a direct procedure for arylboronic esters J. Org. Chem. 1995, 60, 7508-7510
39. Gotoh, O. Substrate recognition sites in cytochrome P450 family 2 (CYP2) proteins inferred from comparative analyses of amino acid and coding nucleotide sequences J. Biol. Chem. 1992, 267, 83-90
40. Mornet, E.; Dupont, J.; Vitek, A.; White, P. C. Characterization of two genes encoding human steroid 11-hydroxylase [P-450(11)] J. Biol. Chem. 1989, 264, 20961-20967 (Pubitemid 20017902)
41. Kawamoto, T.; Mitsuuchi, Y.; Toda, K.; Miyahara, K.; Yokoyama, Y.; Nakao, K.; Hosoda, K.; Yamamoto, Y.; Imura, H.; Shizuta, Y. Cloning of cDNA and genomic DNA for human cytochrome P-45011 FEBS Lett. 1990, 296, 345-349 (Pubitemid 20273823)
42. Kawamoto, T.; Mitsuuchi, Y.; Ohnishi, T.; Ichikawa, Y.; Yokoyama, Y.; Sumimoto, H.; Toda, K.; Miyahara, K.; Kuribayashi, I.; Nakao, K. Cloning and expression of a cDNA for human cytochrome P-450aldo as related to primary aldosteronism. Biochem Biophys. Res. Commun. 1990, 173, 309-316
43. Böttner, B.; Schrauber, H.; Bernhardt, R. Engineering a mineralocorticoid- to a glucocorticoid-synthesizing cytochrome P450 J. Biol. Chem. 1996, 271, 8028-8033 (Pubitemid 26108623)
44. Böttner, B.; Bernhardt, R. Changed ratios of glucocorticoid/ mineralocorticoids caused by point mutations in the putative I-helix regions of CYP11B1 and CYP11B2 Endocr. Res. 1996, 22, 455-561
45. Curnow, K. M.; Mulatero, P.; Emeric-Blanchouin, N.; Aupetit-Faisant, B.; Corvol, P.; Pascoe, L. The amino acid substitutions Ser288Gly and Val320Ala convert the cortisol producing enzyme, CYP11B1, into an aldosterone producing enzyme Nature Struct. Biol. 1997, 4, 32-35 (Pubitemid 27020920)
46. Mulatero, P.; Curnow, K. M.; Aupetit-Taisant, B.; Foekling, M. Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol J. Clin. Endocinol. Metab. 1998, 83, 3996-4001 (Pubitemid 28513586)
47. Böttner, B.; Denner, K.; Bernhardt, R. Conferring aldosterone synthesis to human CYP11B1 by replacing key amino acid residues with CYP11B2-specific ones Eur. J. Biochem. 1998, 252, 458-466 (Pubitemid 28156869)
48. Bechtel, S.; Belkina, N.; Bernhardt, R. The effect of amino acid substitutions I112P, D147E and K152N in CYP11B2 on the catalytic activities of the enzyme Eur. J. Biochem. 2002, 269, 1118-1127 (Pubitemid 34175370)
49. Ghosh, D.; Griswold, J.; Erman, M.; Pangborn, W. Structural basis for androgen specificity and estrogen synthesis in human aromatase Nature 2009, 457, 219-223
50. Ksander, G. M.; Meredith, E.; Monovich, L. G.; Papillon, J.; Firooznia, F.; Hu, Q.-Y. Preparation of condensed imidazole derivatives for the inhibition of aldosterone synthase and aromatase. PCT Int. Appl. WO2007024945, 2007.
51. Papillon, J.; Ksander, G. M; Hu, Q.-Y. Preparation of tetrahydroimidazo[1,5- a ]pyrazine derivatives as aldosterone synthase and/or 11-hydroxylase inhibitors. PCT Int. Appl. WO2007139992, 2007.
52. Hu, Q.-Y.; Ksander, G. M. 4-Imidazolyl-1,2,3,4-tetrahydroquinoline derivatives and their use as aldosterone/11-beta-hydroxylase inhibitors. PCT Int. Appl. WO2008076860, 2008.
53. Hu, Q.-Y.; Ksander, G. M. Organic compounds. PCT Int. Appl. WO2008076862, 2008.
54. 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-1 H -quinolin-2-one derivatives J. Med. Chem. 2008, 51, 8077-8087
55. Ries, C.; Lucas, S.; Heim, R.; Birk, B.; Hartmann, R. W. Selective aldosterone synthase inhibitors reduce aldosterone formation in vitro and in vivo J. Steroid Biochem. Mol. Biol. 2009, 116, 121-126
56. Hartmann, R. W.; Heim, R.; Lucas, S. 6-Pyridin-3-yl-3,4-dihydo-1 H -quinoline-2-one derivatives and related compounds as inhibitors of the human aldosterone synthase CYP11B2. PCT Int. Appl. WO2009135651, 2009.
57. Hu, Q.; Hartmann, R. W. Unpublished results.
58. Denner, K.; Bernhardt, R. Inhibition studies of steroid conversions mediated by human CYP11B1 and CYP11B2 expressed in cell cultures. In Oxygen Homeostasis and Its Dynamics, 1 st ed.; Ishimura, Y.; Shimada, H.; Suematsu, M., Eds.; Springer-Verlag: Tokyo, Berlin, Heidelberg, NY, 1998; pp 231-236.
59. 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, 443-448
60. Lamberts, S. W.; Bruining, H. A.; Marzouk, H.; Zuiderwijk, J.; Uitterlinden, P.; Blijd, J. J.; Hackeng, W. H.; de Jong, F. H. The new aromatase inhibitor CGS-16949A suppresses aldosterone and cortisol production by human adrenal cells in vitro J. Clin. Endocrinol. Metab. 1989, 69, 896-901 (Pubitemid 19245873)
61. Demers, L. M.; Melby, J. C.; Wilson, T. E.; Lipton, A.; Harvey, H. A.; Santen, R. J. The effects of CGS 16949A, an aromatase inhibitor on adrenal mineralocorticoid biosynthesis J. Clin. Endocrinol. Metab. 1990, 70, 1162-1166
62. Heim, R.; Lucas, S.; Grombein, C. M.; Ries, C.; Schewe, K. E.; Negri, M.; MÜller-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, 5064-5074
63. Hille, U. E.; Zimmer, C.; Vock, C. A.; Hartmann, R. W. First selective CYP11B1 inhibitors for the treatment of cortisol-dependent diseases Med. Chem. Lett. 2011, 2, 2-6
64. 17,20-lyase (P450c17) by coexpression of P450c17 with NADPH-cytochrome-P450-reductase in Escherichia coli J. Steroid Biochem. Mol. Biol. 2000, 75, 57-63 (Pubitemid 32155424)
65. Hutschenreuter, T. U.; Ehmer, P. B.; Hartmann, R. W. Synthesis of hydroxy derivatives of highly potent nonsteroidal CYP17 inhibitors as potential metabolites and evaluation of their activity by a noncellular assay using recombinant enzyme J. Enzyme Inhib. Med. Chem. 2004, 19, 17-32 (Pubitemid 38239927)
66. Thompson, E. A.; Siiteri, P. K. Utilization of oxygen and reduced nicotinamide adenine dinucleotide phosphate by human placental microsomes during aromatization of androstenedione J. Biol. Chem. 1974, 249, 5364-5372
67. Molecular Operating Environment MOE 2009.10; CCGIM: Quebec, Canada, 2008; http://www.chemcomp.com
68. Notredame, C.; Higgins, D.; Heringa, J. T-Coffee: A novel method for fast and accurate multiple sequence alignment J. Mol. Biol. 2000, 302, 205-217
69. Cole, C.; Barber, J. D.; Barton, G. J. The JPRED 3 Secondary structure prediction server Nucleic Acids Res. 2008, 36, W197-W201
70. McGuffin, L. J.; Bryson, K.; Jones, D. T. The PSIPRED protein structure prediction server Bioinformatics 2000, 16, 404-405 (Pubitemid 30417087)
71. Eswar, N.; Marti-Renom, M. A.; Webb, B.; Madhusudhan, M. S.; Eramian, D.; Shen, M.; Pieper, U.; Sali, A. Current Protocols in Bioinformatics, John Wiley & Sons, Inc.: New York, 2006.
72. Laskowski, R. A.; MacArthur, M. W.; Moss, D. S.; Thornton, J. M. PROCHECK: a program to check the stereochemical quality of protein structures J. Appl. Crystallogr. 1993, 26, 283-291
73. Wiederstein, M.; Sippl, M. J. ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins Nucleic Acids Res. 2007, 35, W407-W410
74. Sippl, M. J. Recognition of Errors in Three-Dimensional Structures of Proteins Proteins 1993, 17, 355-362 (Pubitemid 23358545)
75. Kramer, B.; Rarey, M.; Lengauer, T. Evaluation of the FlexX incremental construction algorithm for protein-ligand docking Proteins: Struct., Funct., Genet. 1999, 37, 228-241 (Pubitemid 29503004)