Highly potent and selective nonsteroidal dual inhibitors of CYP17/CYP11B2 for the treatment of prostate cancer to reduce risks of cardiovascular diseases

Journal of Medicinal Chemistry

Volumn 56, Issue 15, 2013, Pages 6101-6107

  Pinto Bazurco Mendieta, Mariano A E ^a   Hu, Qingzhong ^a   Engel, Matthias ^a   Hartmann, Rolf W ^a  

^a SAARLAND UNIVERSITY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ALDOSTERONE SYNTHASE; AROMATASE INHIBITOR; CYTOCHROME P450 17; CYTOCHROME P450 3A4; OXYGENASE INHIBITOR;

ARTICLE; CARDIOVASCULAR RISK; HUMAN; IC 50; LIPOPHILICITY; PROSTATE CANCER; STRUCTURE ACTIVITY RELATION; SUZUKI REACTION;

ALDOSTERONE SYNTHASE; ANTINEOPLASTIC AGENTS; CARDIOVASCULAR DISEASES; CELL LINE; CYTOCHROME P-450 CYP3A; HUMANS; MALE; MODELS, MOLECULAR; NAPHTHALENES; PROSTATIC NEOPLASMS; PYRIDINES; STEROID 11-BETA-HYDROXYLASE; STEROID 17-ALPHA-HYDROXYLASE;

EID: 84881420660     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm400484p     Document Type: Article

References (52)

1. Reid, A. H. M.; Attard, G.; Danila, D. C.; Oommen, N. B.; Olmos, D.; Fong, P. C.; Molife, L. R.; Hunt, J.; Messiou, C.; Parker, C.; Dearnaley, D.; Wennenhuis, J. F.; Terstappen, L. W. M. M.; Lee, G.; Kheoh, T.; Molina, A.; Ryan, C. J.; Small, E.; Scher, H. I.; de Bono, J. S. Significant and sustained antitumor activity in postdocetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate J. Clin. Oncol. 2010, 28, 1489-1495
2. Attard, G.; Reid, A. H. M.; Yap, T. A.; Raynaud, F.; Dowsett, M.; Settatree, S.; Barrett, M.; Parker, C.; Martins, V.; Folkerd, E.; Clark, J.; Cooper, C. S.; Kaye, S. B.; Dearnaley, D.; Lee, G.; de Bono, J. S. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven J. Clin. Oncol. 2008, 26, 4563-4571
3. Yin, L.; Hu, Q. CYP17 inhibitors: from promiscuous abiraterone to selective C17-20 lyase inhibitors and multi-targeting agents. Nat. Rev. Urol. 2013, in press
4. Yin, L.; Hu, Q.; Hartmann, R. W. Recent progress in pharmaceutical therapy for castration-resistant prostate cancer Int. J. Mol. Sci. 2013, 14, 13958-13978
5. Schwandt, A.; Garcia, J. A. Complications of androgen deprivation therapy in prostate cancer Curr. Opin. Urol. 2009, 19, 322-326
6. Sánchez-Más, J.; Turpín, M. C.; Lax, A.; Ruipérez, J. A.; Chávarri, M. V.; Pascual-Figal, D. A. Differential actions of eplerenone and spironolactone on the protective effect of testosterone against cardiomyocyte apoptosis in vitro Rev. Esp. Cardiol. 2010, 63, 779-787
7. Nakamura, S.; Yoshimura, M.; Nakayama, M.; Ito, T.; Mizuno, Y.; Harada, E.; Sakamoto, T.; Saito, Y.; Nakao, K.; Yasue, H.; Ogawa, H. Possible association of heart failure status with synthetic balance between aldosterone and dehydroepiandrosterone in human heart Circulation 2004, 110, 1787-1793
8. Traish, A. M.; Abdou, A.; Kypreos, K. E. Androgen deficiency and atherosclerosis: The lipid link Vascul. Pharmacol. 2009, 51, 303-313
9. Smith, M. R.; Finkelstein, J. S.; Mcgovern, F. J.; Zietman, A. L.; Fallon, M. A.; Schoenfeld, D. A.; Kantoff, P. W. Changes in body composition during androgen deprivation therapy for prostate cancer J. Clin. Endocrinol. Metab. 2002, 87, 599-603
10. Kau, M.; Lo, M.; Wang, S.; Tsai, S.; Chen, J.; Chiao, Y.; Yeh, J.; Lin, H.; Shum, A. Y.; Fang, V. S.; Ho, L.; Wang, P. S. Inhibition of aldosterone production by testosterone in male rats Metabolism 1999, 48, 1108-1114
11. Shima, H.; Kawanaka, H.; Yabumoto, Y.; Okamoto, E.; Ikoma, F. A case of 17 alpha-hydroxylase deficiency with chromosomal karyotype 46, XY and high plasma aldosterone concentration Int. Urol. Nephrol. 1991, 23, 611-618
12. De Coster, R.; Mahler, C.; Denis, L.; Coene, M. C.; Caers, I.; Amery, W.; Haelterman, C.; Beerens, D. Effects of high-dose ketoconazole and dexamethasone on ACTH-stimulated adrenal steroidogenesis in orchiectomized prostatic cancer patients Acta Endocrinol. 1987, 115, 265-271
13. Braley, L. M.; Menachery, A. I.; Yao, T.; Mortensen, R. M.; Willams, G. H. Effect of progesterone on aldosterone secretion in rats Endocrinology 1996, 137, 4773-4778
14. Hu, Q.; Yin, L.; Hartmann, R. W. Selective dual inhibitors of CYP19 and CYP11B2: targeting cardiovascular diseases hiding in the shadow of breast cancer J. Med. Chem. 2012, 55, 7080-7089
15. Yin, L.; Hu, Q.; Hartmann, R. W. Tetrahydropyrroloquinolinone type dual inhibitors of aromatase/aldosterone synthase as a novel strategy for breast cancer patients with elevated cardiovascular risks J. Med. Chem. 2013, 56, 460-470
16. Nishikawa, T.; Suematsu, S.; Saito, J.; Soyama, A.; Ito, H.; Kino, T.; Chrousos, G. Human renal mesangial cells produce aldosterone in response to low-density lipoprotein (LDL) J. Steroid Biochem. Mol. Biol. 2005, 96, 309-316
17. Saha, S.; Graessler, J.; Schwarz, P. E. H.; Goettsch, C.; Bornstein, S. R.; Kopprasch, S. Modified high-density lipoprotein modulates aldosterone release through scavenger receptors via extra cellular signal-regulated kinase and Janus kinase-dependent pathways Mol. Cell. Biochem. 2012, 366, 1-10
18. Mizuno, Y.; Yoshimura, M.; Yasue, H.; Sakamoto, T.; Ogawa, H.; Kugiyama, K.; Harada, E.; Nakayama, M.; Nakamura, S.; Ito, T.; Shimasaki, Y.; Saito, Y.; Nakao, K. Aldosterone production is activated in failing ventricle in humans Circulation 2001, 103, 72-77
19. Young, M. J.; Clyne, C. D.; Cole, T. J.; Funder, J. W. Cardiac steroidogenesis in the normal and failing heart J. Clin. Endocrinol. Metab. 2001, 86, 5121-5126
20. Hu, Q.; Negri, M.; Olgen, S.; Hartmann, R. W. The role of fluorine substitution in biphenyl methylene imidazole type CYP17 inhibitors for the treatment of prostate carcinoma ChemMedChem 2010, 5, 899-910
21. Hu, Q.; Yin, L.; Jagusch, C.; Hille, U. E.; Hartmann, R. W. Isopropylidene substitution increases activity and selectivity of biphenyl methylene 4-pyridine type CYP17 inhibitors J. Med. Chem. 2010, 53, 5049-5053
22. Hu, Q.; Negri, M.; Jahn-Hoffmann, K.; Zhuang, Y.; Olgen, S.; Bartels, M.; Müller-Vieira, U.; Lauterbach, T.; Hartmann, R. W. Synthesis, biological evaluation, and molecular modeling studies of methylene imidazole substituted biaryls as inhibitors of human 17α-hydroxylase-17,20-lyase (CYP17)-Part II: Core rigidification and influence of substituents at the methylene bridge Bioorg. Med. Chem. 2008, 16, 7715-7727
23. Hille, U. E.; Hu, Q.; Vock, C.; Negri, M.; Bartels, M.; Mueller-Vieira, U.; Lauterbach, T.; Hartmann, R. W. Novel CYP17 inhibitors: Synthesis, biological evaluation, structure-activity relationships and modeling of methoxy- and hydroxy-substituted methyleneimidazolyl biphenyls Eur. J. Med. Chem. 2009, 44, 2765-2775
24. Hu, Q.; Jagusch, C.; Hille, U. E.; Haupenthal, J.; Hartmann, R. W. Replacement of imidazolyl by pyridyl in biphenyl methylenes results in selective CYP17 and dual CYP17/CYP11B1 inhibitors for the treatment of prostate cancer J. Med. Chem. 2010, 53, 5749-5758
25. Jagusch, C.; Negri, M.; Hille, U. E.; Hu, Q.; Bartels, M.; Jahn-Hoffmann, K.; Pinto-Bazurco Mendieta, M. A. E.; Rodenwaldt, B.; Müller-Vieira, U.; Schmidt, D.; Lauterbach, T.; Recanatini, M.; Cavalli, A.; Hartmann, R. W. Synthesis, biological evaluation and molecular modeling studies of methyleneimidazole substituted biaryls as inhibitors of human 17α-hydroxylase-17,20-lyase (CYP17)-Part I: heterocyclic modifications of the core structure Bioorg. Med. Chem. 2008, 16, 1992-2010
26. Pinto-Bazurco Mendieta, M. A. E.; Negri, M.; Hu, Q.; Hille, U. E.; Jagusch, C.; Jahn-Hoffmann, K.; Müller-Vieira, U.; Schmidt, D.; Lauterbach, T.; Hartmann, R. W. CYP17 inhibitors. Annulations of additional rings in methylene imidazole substituted biphenyls: synthesis, biological evaluation and molecular modeling Arch. Pharm. (Weinheim, Ger.) 2008, 341, 597-609
27. Hille, U. E.; Hu, Q.; Pinto-Bazurco Mendieta, M. A. E.; Bartels, M.; Vock, C. A.; Lauterbach, T.; Hartmann, R. W. Steroidogenic cytochrome P450 (CYP) enzymes as drug targets: Combining substructures of known CYP inhibitors leads to compounds with different inhibitory profile C. R. Chim. 2009, 12, 1117-1126
28. Yin, L.; Lucas, S.; Maurer, F.; Kazmaier, U.; Hu, Q.; Hartmann, R. W. Novel imidazol-1-ylmethyl substituted 1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij] quinolin-4-ones as potent and selective CYP11B1 inhibitors for the treatment of Cushing's syndrome J. Med. Chem. 2012, 55, 6629-6633
29. Emmerich, J.; Hu, Q.; Hanke, N.; Hartmann, R. W. Cushing's syndrome: Development of highly potent and selective CYP11B1 inhibitors of the (pyridylmethyl)pyridine type J. Med. Chem. 2013, 10.1021/jm400240r
30. 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, 6632-6642
31. 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, 8077-8087
32. 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
33. Gobbi, S.; Hu, Q.; Negri, M.; Zimmer, C.; Belluti, F.; Rampa, A.; Hartmann, R. W.; Bisi, A. Modulation of cytochromes P450 with xanthone-based molecules: from aromatase to aldosterone synthase and steroid 11β-hydroxylase inhibition J. Med. Chem. 2013, 56, 1723-1729
34. Roumen, L.; Peeters, J. W.; Emmen, J. M. A.; Beugels, I. P. E.; Custers, E. M. G.; de Gooyer, M.; Plate, R.; Pieterse, K.; Hilbers, P. A. J.; Smits, J. F. M.; Vekemans, J. A. J.; Leysen, D.; Ottenheijm, H. C. J.; Janssen, H. M.; Hermans, J. J. R. Synthesis, biological evaluation, and molecular modeling of 1-benzyl-1H-imidazoles as selective inhibitors of aldosterone synthase (CYP11B2) J. Med. Chem. 2010, 53, 1712-1725
35. 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
36. 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 (CYP11B2) for the treatment of congestive heart failure and myocardial fibrosis J. Med. Chem. 2006, 49, 2222-2231
37. Yin, L.; Hu, Q.; Hartmann, R. W. 3-Pyridinyl substituted aliphatic cycles as CYP11B2 inhibitors: aromaticity abolishment of the core significantly increased selectivity over CYP1A2 PLoS ONE 2012, 7 (11) e48048
38. Gobbi, S.; Cavalli, A.; Negri, M.; Schewe, K. E.; Belluti, F.; Piazzi, L.; Hartmann, R. W.; Recanatini, M.; Bisi, A. Imidazolylmethylbenzophenones as highly potent aromatase inhibitors J. Med. Chem. 2007, 50, 3420-3422
39. Leze, M. P.; Le Borgne, M.; Pinson, P.; Palusczak, A.; Duflos, M.; Le Baut, G.; Hartmann, R. W. Synthesis and biological evaluation of 5-[(aryl)(1H-imidazol-1-yl)methyl]-1H-indoles: potent and selective aromatase inhibitors Bioorg. Med. Chem. Lett. 2006, 16, 1134-1137
40. Abadi, A. H.; Abou-Seri, S. M.; Hu, Q.; Negri, M.; Hartmann, R. W. Synthesis and biological evaluation of imidazolylmethyl-acridones as cytochrome P-450 enzymes inhibitors MedChemComm 2012, 3, 663-666
41. Yin, L.; Hu, Q. Drug discovery for breast cancer and coinstantaneous cardiovascular disease: What is the future? Future Med. Chem. 2013, 5, 359-362
42. Picard, F.; Baston, E.; Reichert, W.; Hartmann, R. W. Synthesis of N-substituted piperidine-4-(benzylidene-4-carboxylic acids) and evaluation as inhibitors of steroid-5α-reductase type 1 and 2 Bioorg. Med. Chem. 2000, 8, 1479-1487
43. Bey, E.; Marchais-Oberwinkler, S.; Negri, M.; Kruchten, P.; Oster, A.; Klein, T.; Spadaro, A.; Werth, R.; Frotscher, M.; Birk, B.; Hartmann, R. W. New Insights into the SAR and binding modes of bis(hydroxyphenyl)thiophenes and -benzenes: influence of additional substituents on 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) inhibitory activity and selectivity J. Med. Chem. 2009, 52, 6724-6743
44. Bey, E.; Marchais-Oberwinkler, S.; Kruchten, P.; Frotscher, M.; Werth, R.; Oster, A.; Algül, O.; Neugebauer, A.; Hartmann, R. W. Design, synthesis and biological evaluation of bis(hydroxyphenyl) azoles as potent and selective non-steroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) for the treatment of estrogen-dependent diseases Bioorg. Med. Chem. 2008, 16, 6423-6435
45. DeVore, N. M.; Scott, E. E. Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001 Nature 2012, 482, 116-120
46. Strushkevich, N.; Gilep, A. A.; Shen, L.; Arrowsmith, C. H.; Edwards, A. M.; Usanov, S. A.; Park, H. W. Structural insights into aldosterone synthase substrate specificity and targeted inhibition Mol. Endocrinol. 2013, 27, 315-324
47. Wilcken, R.; Zimmermann, M. O.; Lange, A.; Joerger, A. C.; Boeckler, F. M. Principles and applications of halogen bonding in medicinal chemistry and chemical biology J. Med. Chem. 2013, 56, 1363-1388
48. Müller, K.; Faeh, C.; Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition Science 2007, 317, 1881-1886
49. Ohe, T.; Miyaura, N.; Suzuki, A. Palladium-catalyzed cross-coupling reaction of organoboron compounds with organic triflates J. Org. Chem. 1993, 58, 2201-2208
50. Ehmer, P. B.; Jose, J.; Hartmann, R. W. Development of a simple and rapid assay for the evaluation of inhibitors of human 17α-hydroxylase-C(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
51. Ehmer, P. B.; Bureik, M.; Bernhardt, R.; Müller, U.; Hartmann, R. W. Development of a test system synthase (CYP11B2): Screening in fission yeast and evaluation of selectivity in V79 cells J. Steroid Biochem. Mol. Biol. 2002, 81, 173-179
52. 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