Bicyclic substituted hydroxyphenylmethanones as novel inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) for the treatment of estrogen-dependent diseases

Journal of Medicinal Chemistry

Volumn 53, Issue 22, 2010, Pages 8176-8186

  Oster, Alexander ^a   Hinsberger, Stefan ^a   Werth, Ruth ^a   Marchais Oberwinkler, Sandrine ^a   Frotscher, Martin ^a   Hartmann, Rolf W ^a  

^a SAARLAND UNIVERSITY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

(3 HYDROXYPHENYL)[5 (3 HYDROXYPHENYL) 2 THIENYL]METHANONE; (3 HYDROXYPHENYL)[5 (4 HYDROXYPHENYL) 2 THIENYL]METHANONE; 17BETA HYDROXYSTEROID DEHYDROGENASE TYPE 1; [2 (4 HYDROXY 3 METHYLPHENYL) 1,3 THIAZOL 5 YL](3 HYDROXYPHENYL)METHANONE; [5 (3 CHLORO 4 HYDROXYPHENYL) 2 THIENYL](3 HYDROXYPHENYL)METHANONE; [5 (3 ETHYL 4 HYDROXYPHENYL) 2 THIENYL](3 HYDROXYPHENYL)METHANONE; [5 (3 FLUORO 4 HYDROXYPHENYL) 2 THIENYL](3 HYDROXYPHENYL)METHANONE; [5 (4 HYDROXY 3 METHYLPHENYL) 2 THIENYL](3 HYDROXYPHENYL)METHANONE; DEXTROMETHORPHAN; ENZYME INHIBITOR; ESTRADIOL; ESTROGEN RECEPTOR ALPHA; ESTROGEN RECEPTOR BETA; ESTRONE; HYDROXYPHENYLMETHANONE DERIVATIVE; OXIDOREDUCTASE; UNCLASSIFIED DRUG; VERAPAMIL;

ARTICLE; BINDING AFFINITY; CRYSTAL STRUCTURE; DRUG CLEARANCE; DRUG DESIGN; DRUG HALF LIFE; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; FRIEDEL CRAFTS REACTION; HUMAN; HUMAN CELL; HYDROGEN BOND; IC 50; IN VITRO STUDY; LIVER MICROSOME; PHARMACOPHORE; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION; SUZUKI REACTION;

CELL LINE, TUMOR; DRUG DESIGN; DRUG STABILITY; ESTRADIOL DEHYDROGENASES; ESTROGEN RECEPTOR ALPHA; ESTROGEN RECEPTOR BETA; FEMALE; HUMANS; MICROSOMES, LIVER; PHENOLS; PLACENTA; PREGNANCY; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES; THIOPHENES;

EID: 78649513552     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm101073q     Document Type: Article

References (54)

1. Travis, R. C.; Key, T. J. Oestrogen exposure and breast cancer risk Breast Cancer Res. 2003, 5, 239-247
2. Dizerega, G. S.; Barber, D. L.; Hodgen, G. D. Endometriosis: role of ovarian steroids in initiation, maintenance and suppression Fertil. Steril. 1980, 33, 649-653
3. Herold, C. I.; Blackwell, K. L. Aromatase inhibitors for breast cancer: proven efficacy across the spectrum of disease Clin. Breast Cancer 2008, 8, 50-64
4. Gobbi, S.; Zimmer, C.; Belluti, F.; Rampa, A.; Hartmann, R. W.; Recanatini, M.; Bisi, A. Novel highly potent and selective nonsteroidal aromatase inhibitors: synthesis, biological evaluation and structure-activity relationships investigation J. Med. Chem. 2010, 53, 5347-5351
5. Le Borgne, M.; Marchand, P.; Delevoye-Seiller, B.; Robert, J. M.; Le Baut, G.; Hartmann, R. W.; Palzer, M. New selective nonsteroidal aromatase inhibitors: synthesis and inhibitory activity of 2,3 or 5-(alpha-azolylbenzyl)-1 H -indoles Bioorg. Med. Chem. Lett. 1999, 9, 333-336
6. 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, Ger.) 1997, 330, 141-145
7. Schuster, D.; Laggner, C.; Steindl, T. M.; Palusczak, A.; Hartmann, R. W.; Langer, T. Pharmacophore modeling and in silico screening for new P450 19 (aromatase) inhibitors J. Chem. Inf. Model. 2006, 46, 1301-1311
8. Leonetti, F.; Favia, A.; Rao, A.; Aliano, R.; Paluszcak, A.; Hartmann, R. W.; Carotti, A. Design, synthesis, and 3D QSAR of novel potent and selective aromatase inhibitors J. Med. Chem. 2004, 47, 6792-6803
9. Aidoo-Gyamfi, K.; Cartledge, T.; Shah, K.; Ahmed, S. Estrone sulfatase and its inhibitors Anticancer Agents Med. Chem. 2009, 9, 599-612
10. Gunnarsson, C.; Hellqvist, E.; Stål, O. 17beta-Hydroxysteroid dehydrogenases involved in local oestrogen synthesis have prognostic significance in breast cancer Br. J. Cancer 2005, 92, 547-552
11. Miyoshi, Y.; Ando, A.; Shiba, E.; Taguchi, T.; Tamaki, Y.; Noguchi, S. Involvement of up-regulation of 17beta-hydroxysteroid dehydrogenase type 1 in maintenance of intratumoral high estradiol levels in postmenopausal breast cancers Int. J. Cancer 2001, 94, 685-689
12. Šmuc, T.; Pucelj Ribič, M.; Šinkovec, J.; Husen, B.; Thole, H.; Lanišnik Rižner, T. Expression analysis of the genes involved in estradiol and progesterone action in human ovarian endometriosis Gynecol. Endocrinol. 2007, 23, 105-111
13. Aggarwal, S.; Thareja, S.; Verma, A.; Bhardwaj, T. R.; Kumar, M. An overview on 5alpha-reductase inhibitors Steroids 2010, 75, 109-153
14. Picard, F.; Schulz, T.; Hartmann, R. W. 5-Phenyl substituted 1-methyl-2-pyridones and 4′-substituted biphenyl-4-carboxylic acids. synthesis and evaluation as inhibitors of steroid-5alpha-reductase type 1 and 2 Bioorg. Med. Chem. 2002, 10, 437-448
15. Baston, E.; Palusczak, A.; Hartmann, R. W. 6-Substituted 1 H -quinolin-2-ones and 2-methoxy-quinolines: synthesis and evaluation as inhibitors of steroid 5alpha reductases types 1 and 2 Eur. J. Med. Chem. 2000, 35, 931-940
16. Baston, E.; Hartmann, R. W. N -Substituted 4-(5-indolyl)benzoic acids. Synthesis and evaluation of steroid 5alpha-reductase type I and II inhibitory activity Bioorg. Med. Chem. Lett. 1999, 9, 1601-1606
17. Haller, F.; Moman, E.; Hartmann, R. W.; Adamski, J.; Mindnich, R. Molecular framework of steroid/retinoid discrimination in 17beta-hydroxysteroid dehydrogenase type 1 and photoreceptor-associated retinol dehydrogenase J. Mol. Biol. 2010, 399, 255-267
18. Marchais-Oberwinkler, S.; Henn, C.; Möller, G.; Klein, T.; Lordon, M.; Negri, M.; Oster, A.; Spadaro, A.; Werth, R.; Xu, K.; Frotscher, M.; Hartmann, R. W.; Adamski, J. 17beta-Hydroxysteroid dehydrogenases (17beta-HSD): genes, protein structures, novel therapeutic targets and recent progress in inhibitor development. J. Steroid Biochem. Mol. Biol. 2010, submitted and references therein.
19. Moore, D. M.; Kalvakolanu, D. V.; Lippman, S. M.; Kavanagh, J. J.; Hong, W. K.; Borden, E. C.; Paredes-Espinoza, M.; Krakoff, I. H. Retinoic acid and interferon in human cancer: mechanistic and clinical studies Semin. Hematol. 1994, 31, 31-37
20. Husen, B.; Huhtinen, K.; Poutanen, M.; Kangas, L.; Messinger, J.; Thole, H. Evaluation of inhibitors for 17beta-hydroxysteroid dehydrogenase type 1 in vivo in immunodeficient mice inoculated with MCF-7 cells stably expressing the recombinant human enzyme Mol. Cell. Endocrinol. 2006, 248, 109-113
21. Husen, B.; Huhtinen, K.; Saloniemi, T.; Messinger, J.; Thole, H. H.; Poutanen, M. Human hydroxysteroid (17-beta) dehydrogenase 1 expression enhances estrogen sensitivity of MCF-7 breast cancer cell xenografts Endocrinology 2006, 147, 5333-5339
22. Day, J. M.; Foster, P. A.; Tutill, H. J.; Parsons, M. F.; Newman, S. P.; Chander, S. K.; Allan, G. M.; Lawrence, H. R.; Vicker, N.; Potter, B. V.; Reed, M. J.; Purohit, A. 17beta-Hydroxysteroid dehydrogenase type 1, and not type 12, is a target for endocrine therapy of hormone-dependent breast cancer Int. J. Cancer 2008, 122, 1931-1940
23. Lamminen, T.; Saloniemi, T.; Huhtinen, K.; Koskimies, P.; Messinger, J.; Husen, B.; Thole, H.; Poutanen, M. In vivo mouse model for analysis of hydroxysteroid (17beta) dehydrogenase 1 inhibitors Mol. Cell. Endocrinol. 2009, 301, 158-162
24. Grümmer, R.; Schwarzer, F.; Bainczyk, K.; Hess-Stumpp, H.; Regidor, P. A.; Schindler, A. E.; Winterhager, E. Peritoneal endometriosis: validation of an in vivo model Hum. Reprod. 2001, 16, 1736-1743
25. Einspanier, A.; Lieder, K.; Bruns, A.; Husen, B.; Thole, H.; Simon, C. Induction of endometriosis in the marmoset monkey (Callithrix jacchus) Mol. Hum. Reprod. 2006, 12, 291-299
26. Poirier, D. Advances in development of inhibitors of 17beta hydroxysteroid dehydrogenases Anticancer Agents Med. Chem. 2009, 9, 642-660 and references therein.
27. Brožic, P.; Lanišnik Rižner, T.; Gobec, S. Inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 Curr. Med. Chem. 2008, 15, 137-150 and references therein.
28. Day, J. M.; Tutill, H. J.; Purohit, A.; Reed, M. J. Design and validation of specific inhibitors of 17beta-hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis Endocr. Relat. Cancer 2008, 15, 665-692 and references therein.
29. Schuster, D.; Nashev, L. G.; Kirchmair, J.; Laggner, C.; Wolber, G.; Langer, T.; Odermatt, A. Discovery of nonsteroidal 17beta-hydroxysteroid dehydrogenase 1 inhibitors by pharmacophore-based screening of virtual compound libraries J. Med. Chem. 2008, 51, 4188-4199
30. Michiels, P. J. A.; Ludwig, C.; Stephan, M.; Fischer, C.; Möller, G.; Adamski, J.; van Dongen, M.; Thole, H.; Günther, U. L. Ligand based NMR spectra demonstrate an additional phytoestrogen binding site for 17 beta-hydroxysteroid dehydrogenase type-1 J. Steroid Biochem. Mol. Biol. 2009, 117, 93-98
31. Negri, M.; Recanatini, M.; Hartmann, R. W. Insights in 17beta-HSD1 enzyme kinetics and ligand binding by dynamic motion investigation PLoS One 2010, 5, e 12026
32. Brožic, P.; Kocbek, P.; Sova, M.; Kristl, J.; Martens, S.; Adamski, J.; Gobec, S.; Lanišnik Rižner, T. Flavonoids and cinnamic acid derivatives as inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 Mol. Cell. Endocrinol. 2009, 301, 229-234
33. Messinger, J.; Hirvelä, L.; Husen, B.; Kangas, L.; Koskimies, P.; Pentikäinen, O.; Saarenketo, P.; Thole, H. New inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 Mol. Cell. Endocrinol. 2006, 248, 192-198
34. Karkola, S.; Lilienkampf, A.; Wähälä, K. A 3D QSAR model of 17beta-HSD1 inhibitors based on a thieno[2,3- d ]pyrimidin-4(3 H)-one core applying molecular dynamics simulations and ligand-protein docking ChemMedChem 2008, 3, 461-472
35. Frotscher, M.; Ziegler, E.; Marchais-Oberwinkler, S.; Kruchten, P.; Neugebauer, A.; Fetzer, L.; Scherer, C.; Müller-Vieira, U.; Messinger, J.; Thole, H.; Hartmann, R. W. Design, synthesis and biological evaluation of (hydroxyphenyl)-naphthalene and quinoline derivatives: potent and selective nonsteroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) for the treatment of estrogen-dependent diseases J. Med. Chem. 2008, 51, 2158-2169 (Pubitemid 351503271)
36. Marchais-Oberwinkler, S.; Kruchten, P.; Frotscher, M.; Ziegler, E.; Neugebauer, A.; Bhoga, U. D.; Bey, E.; Müller-Vieira, U.; Messinger, J.; Thole, H.; Hartmann, R. W. Substituted 6-phenyl-2-naphthols. Potent and selective nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17beta-HSD1): design, synthesis, biological evaluation and pharmacokinetics J. Med. Chem. 2008, 51, 4685-4698
37. Marchais-Oberwinkler, S.; Frotscher, M.; Ziegler, E.; Werth, R.; Kruchten, P.; Messinger, J.; Thole, H.; Hartmann, R. W. Structure-activity study in the class of 6-(3′-hydroxyphenyl)naphthalenes leading to an optimization of a pharmacophore model for 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) inhibitors Mol. Cell. Endocrinol. 2009, 301, 205-211
38. Kruchten, P.; Werth, R.; Marchais-Oberwinkler, S.; Frotscher, M.; Hartmann, R. W. Development of a biological screening system for the evaluation of highly active and selective 17beta-HSD1-inhibitors as potential therapeutic agents Mol. Cell. Endocrinol. 2009, 301, 154-157
39. Marchais-Oberwinkler, S.; Wetzel, M.; Ziegler, E.; Kruchten, P.; Werth, R.; Hartmann, R. W.; Frotscher, M. New drug-like hydroxyphenylnaphthol steroidomimetics as potent and selective 17beta-HSD1 inhibitors for the treatment of estrogen dependent diseases. J. Med. Chem. 2010, submitted for publication.
40. Bey, E.; Marchais-Oberwinkler, S.; Kruchten, P.; Frotscher, M.; Werth, R.; Oster, A.; Algul, O.; Neugebauer, A.; Hartmann, R. W. Design, synthesis and biological evaluation of bis(hydroxyphenyl) azoles as potent and selective nonsteroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) for the treatment of estrogen-dependent diseases Bioorg. Med. Chem. 2008, 16, 6423-6435 (Pubitemid 351783414)
41. Bey, E.; Marchais-Oberwinkler, S.; Werth, R.; Negri, M.; Al-Soud, Y. A.; Kruchten, P.; Oster, A.; Frotscher, M.; Birk, B.; Hartmann, R. W. Design, synthesis, biological evaluation and pharmacokinetics of bis(hydroxyphenyl) substituted azoles, thiophenes, benzenes and aza-benzenes as potent and selective non-steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) J. Med. Chem. 2008, 51, 6725-6739
42. Al-Soud, Y. A.; Bey, E.; Oster, A.; Marchais-Oberwinkler, S.; Werth, R.; Kruchten, P.; Frotscher, M.; Hartmann, R. W. The role of the heterocycle in bis(hydroxyphenyl)triazoles for inhibition of 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type 1 and type 2 Mol. Cell. Endocrinol. 2009, 301, 212-215
43. Bey, E.; Marchais-Oberwinkler, S.; Negri, M.; Kruchten, P.; Oster, 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. Kruchten, P.; Werth, R.; Bey, E.; Oster, A.; Marchais-Oberwinkler, S.; Frotscher, M.; Hartmann, R. W. Selective inhibition of 17beta-hydroxysteroid dehydrogenase type 1 (17betaHSD1) reduces estrogen responsive cell growth of T47-D breast cancer cells J. Steroid Biochem. Mol. Biol. 2009, 114, 200-206
45. Kruchten, P.; Werth, R.; Marchais-Oberwinkler, S.; Bey, E.; Ziegler, E.; Oster, A.; Frotscher, M.; Hartmann, R. W. Development of biological assays for the identification of selective inhibitors of estradiol formation from estrone in rat liver preparations C. R. Chim. 2009, 12, 1110-1116
46. Oster, A.; Klein, T.; Werth, R.; Kruchten, P.; Bey, E.; Negri, M.; Marchais-Oberwinkler, S.; Frotscher, M.; Hartmann, R. W. Novel estrone mimetics with high 17beta-HSD1 inhibitory activity Bioorg. Med. Chem. 2010, 18, 3494-3505
47. Mazumdar, M.; Fournier, D.; Zhu, D. W.; Cadot, C.; Poirier, D.; Lin, S. X. Binary and ternary crystal structure analyses of a novel inhibitor with 17beta-HSD type 1: a lead compound for breast cancer therapy Biochem. J. 2009, 424, 357-366
48. Miyaura, N.; Suzuki, A. The palladium catalysed cross-coupling reaction of phenylboronic acid with haloarenes in the presence of bases Synth. Commun. 1995, 11, 513-519
49. Fink, B. E.; Mortensen, D. S.; Stauffer, S. R.; Aron, Z. D.; Katzenellenbogen, J. A. Novel structural templates for estrogen-receptor ligands and prospects for combinatorial synthesis of estrogens Chem. Biol. 1999, 6, 205-219
50. Allan, G. M.; Vicker, N.; Lawrence, H. R.; Tutill, H. J.; Day, J. M.; Huchet, M.; Ferrandis, E.; Reed, M. J.; Purohit, A.; Potter, B. V. Novel inhibitors of 17beta-hydroxysteroid dehydrogenase type 1: templates for design Bioorg. Med. Chem. 2008, 16, 4438-4456
51. Bhatt, M. V.; Kulkarni, S. U. Cleavage of ethers Synthesis 1983, 249-282
52. Czaplewski, L. G.; Collins, I.; Boyd, E. A.; Brown, D.; East, S. P.; Gardiner, M.; Fletcher, R.; Haydon, D. J.; Henstock, V.; Ingram, P.; Jones, C.; Noula, C.; Kennison, L.; Rockley, C.; Rose, V.; Thomaides-Brears, H. B.; Ure, R.; Whittaker, M.; Stokes, N. R. Antibacterial alkoxybenzamide inhibitors of the essential bacterial cell division protein FtsZ Bioorg. Med. Chem. Lett. 2009, 19, 524-527
53. Morgan, B. P.; Galdamez, G. A.; Gilliard, R. J., Jr.; Smith, R. C. Canopied trans-chelating bis(N -heterocyclic carbene) ligand: synthesis, structure and catalysis Dalton Trans. 2009, 2020-2028
54. Zimmermann, J.; Liebl, R.; von Angerer, E. 2,5-Diphenylfuran-based pure antiestrogens with selectivity for the estrogen receptor alpha J. Steroid Biochem. Mol. Biol. 2005, 94, 57-66