Novel N-methylsulfonamide and retro-N-methylsulfonamide derivatives as 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) inhibitors with good ADME-related physicochemical parameters

European Journal of Medicinal Chemistry

Volumn 69, Issue , 2013, Pages 201-215

  Perspicace, Enrico ^a   Giorgio, Annalaura ^a,b   Carotti, Angelo ^b   Marchais Oberwinkler, Sandrine ^a   Hartmann, Rolf W ^a,c  

^a SAARLAND UNIVERSITY   (Germany)

^b UNIVERSITY OF BARI   (Italy)

^c SAARLAND UNIVERSITY   (Germany)

Author keywords

17 Hydroxysteroid dehydrogenase type 2; ADME properties; Aqueous solubility; Enzyme inhibition; Log P; N Methylsulfonamide derivatives; Osteoporosis; pKa; Retro N methylsulfonamide derivatives; Structure activity relationship; Structure property relationship

Indexed keywords

2' METHOXY N METHYL N PHENYL[1,1' BIPHENYL] 4 SULFONAMIDE; 2' METHOXY N(3 METHOXYPHENYL)N METHYL[1,1' BIPHENYL] 4 SULFONAMIDE; 3 BROMO N(3 METHOXYPHENYL)N METHYLBENZENESULFONAMIDE; 3 METHOXY N(3' METHOXY[1,1' BIPHENYL] 4 YL)N METHYLBENZENESULFONAMIDE; 3' HYDROXY N(3 HYDROXYBENZYL)N METHYL[1,1' BIPHENYL] 4 SULFONAMIDE; 3' HYDROXY N(3 HYDROXYPHENYL)N METHYL[1,1' BIPHENYL] 4 SULFONAMIDE; 3' HYDROXY N(3 METHOXYPHENYL)N METHYL[1,1' BIPHENYL] 4 SULFONAMIDE; 3' METHOXY N(2 METHOXYPHENYL)N METHYL[1,1' BIPHENYL] 4 SULFONAMIDE; 3' METHOXY N(3 METHOXYPHENYL)N METHYL[1,1' BIPHENYL] 4 SULFONAMIDE; 3' METHOXY N(4 METHOXYPHENYL)N METHYL[1,1' BIPHENYL] 4 SULFONAMIDE; 4 BROMO N METHYL N PHENYLBENZENESULFONAMIDE; 4 BROMO N(2 METHOXYPHENYL)N METHYLBENZENESULFONAMIDE; 4 BROMO N(3 HYDROXYPHENYL)N METHYLBENZENESULFONAMIDE; 4 BROMO N(3 METHOXYBENZYL)N METHYLBENZENESULFONAMIDE; 4 BROMO N(3 METHOXYPHENYL)N METHYLBENZENESULFONAMIDE; 4 BROMO N(4 METHOXYPHENYL)N METHYLBENZENESULFONAMIDE; 4' METHOXY N(3 METHOXYPHENYL)N METHYL[1,1' BIPHENYL] 4 SULFONAMIDE; ENZYME INHIBITOR; N(3 BROMOPHENYL) 3 METHOXY N METHYLBENZENESULFONAMIDE; N(3 BROMOPHENYL) 4 FLUORO 3 METHOXY N METHYLBENZENESULFONAMIDE; N(3 HYDROXYPHENYL) 3' METHOXY N METHYL[1,1' BIPHENYL] 4 SULFONAMIDE; N(3 HYDROXYPHENYL)N METHYL 4 (THIOPHEN 2 YL)BENZENESULFONAMIDE; N(3 HYDROXYPHENYL)N,3' DIMETHYL[1,1' BIPHENYL] 4 SULFONAMIDE; N(3 METHOXYPHENYL)N METHYL 4 (THIOPHEN 2 YL)BENZENESULFONAMIDE; N(3 METHOXYPHENYL)N METHYL 4 (THIOPHEN 3 YL)BENZENESULFONAMIDE; N(4 BROMOPHENYL) 3 METHOXY N METHYLBENZENESULFONAMIDE; N(4 HYDROXYPHENYL)N METHYL 4 (PYRIDIN 3 YL)BENZENESULFONAMIDE; SULFONAMIDE; TESTOSTERONE 17BETA DEHYDROGENASE INHIBITOR; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ACIDITY; ARTICLE; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; EVALUATION; IC 50; LIPOPHILICITY; MICROWAVE IRRADIATION; PHYSICAL CHEMISTRY; PKA;

17Β-HSD1; 17Β-HSD2; 17Β-HYDROXYSTEROID DEHYDROGENASE TYPE 1; 17Β-HYDROXYSTEROID DEHYDROGENASE TYPE 2; A-DIONE; ABSORPTION, DISTRIBUTION, METABOLISM AND ELIMINATION; ADME; ADME PROPERTIES; ANDROSTENEDIONE; AQUEOUS SOLUBILITY; BDBNXSRLAWWJLY-UHFFFAOYSA-N; BIAIGWIQNONMAW-UHFFFAOYSA-N; BOLMQRQNXIVUII-UHFFFAOYSA-N; CJDUVKSVPAJUGB-UHFFFAOYSA-N; CVLJEOBEVPFRFY-UHFFFAOYSA-N; E2; ENZYME INHIBITION; ESTRADIOL; FRHNMKNFWOBLST-UHFFFAOYSA-N; FRINQDZEYLJNHP-UHFFFAOYSA-N; FWBCDWYBDIBPOB-UHFFFAOYSA-N; HEWWOXLVHWOXCV-UHFFFAOYSA-N; HGIDCXXUTBGJIY-UHFFFAOYSA-N; HJIPMYQQHXXUJR-UHFFFAOYSA-N; ICFIUYRSPOQXRW-UHFFFAOYSA-N; KIOHYPYDGDIUEP-UHFFFAOYSA-N; KQJBQVYEJBYXHB-UHFFFAOYSA-N; LOG P; MBUYCTFZQRXWEF-UHFFFAOYSA-N; MOLECULAR WEIGHT; MW; N-METHYLSULFONAMIDE DERIVATIVES; NIURFBGRZZFAIE-UHFFFAOYSA-N; OB; OC; OIOMZDRZILJASQ-UHFFFAOYSA-N; OSTEOBLAST; OSTEOCLAST; OSTEOPOROSIS; PKA; PLBSKHREONAECB-UHFFFAOYSA-N; QVMDQMXJSFGISQ-UHFFFAOYSA-N; RETRO-N-METHYLSULFONAMIDE DERIVATIVES; ROQZUUAYDVZNHP-UHFFFAOYSA-N; RQRVWLDFSXDEPX-UHFFFAOYSA-N; RSBNDQRTKQAMHN-UHFFFAOYSA-N; SELECTIVITY FACTOR; SF; STRUCTURE-ACTIVITY RELATIONSHIP; STRUCTURE-PROPERTY RELATIONSHIP; T; TESTOSTERONE; TOPOLOGICAL POLAR SURFACE AREA; TPSA; XAUKOQDTIZJUFD-UHFFFAOYSA-N; YFYJPTJQMCYDHJ-UHFFFAOYSA-N;

CHEMISTRY, PHYSICAL; DOSE-RESPONSE RELATIONSHIP, DRUG; ENZYME INHIBITORS; ESTRADIOL DEHYDROGENASES; HUMANS; MOLECULAR STRUCTURE; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES;

EID: 84883610311     PISSN: 02235234     EISSN: 17683254     Source Type: Journal    
DOI: 10.1016/j.ejmech.2013.08.026     Document Type: Article

References (52)

1. G. Karaguzel, and M.F. Holick Diagnosis and treatment of osteopenia Rev. Endocr. Metab. Disord. 11 2010 237 251
2. Osteoporosis prevention, diagnosis, and therapy NIH Consensus Statement 2000 3 36
3. S.R. Cummings, and L.J. Melton Epidemiology and outcomes of osteoporotic fractures Lancet 359 2002 1761 1767
4. S.C. Manolagas Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis Endocr. Rev. 21 2000 115 137 (Pubitemid 32275592)
5. C.M. Bagi, J. Wood, D. Wilkie, and B. Dixon Effect of 17β-hydroxysteroid dehydrogenase type 2 inhibitor on bone strength in ovariectomized cynomolgus monkeys J. Musculoskelet. Neuronal Interact. 8 2008 267 280
6. R. Marcus, M. Wong, H. Heath 3rd, and J.L. Stock Antiresorptive treatment of postmenopausal osteoporosis: comparison of study designs and outcomes in large clinical trials with fracture as an endpoint Endocr. Rev. 23 2002 16 37 (Pubitemid 34185305)
7. E. Orwoll, M. Ettinger, S. Weiss, P. Miller, D. Kendler, J. Graham, S. Adami, K. Weber, R. Lorenc, P. Pietschmann, K. Vandormael, and A. Lombardi Alendronate for the treatment of osteoporosis in men N. Engl. J. Med. 343 2000 604 610 (Pubitemid 30659471)
8. J.D. Ringe, H. Faber, P. Farahmand, and A. Dorst Efficacy of risedronate in men with primary and secondary osteoporosis: results of a 1-year study Rheumatol. Int. 26 2006 427 431
9. L. Wu, M. Einstein, W.M. Geissler, H.K. Chan, K.O. Elliston, and S. Andersson Expression cloning and characterization of human 17β- hydroxysteroid dehydrogenase type 2, a microsomal enzyme possessing 20 alpha-hydroxysteroid dehydrogenase activity J. Biol. Chem. 268 1993 12964 12969 (Pubitemid 23182471)
10. M.L. Lu, Y.W. Huang, and S.X. Lin Purification, reconstitution, and steady-state kinetics of the trans-membrane 17β-hydroxysteroid dehydrogenase 2 J. Biol. Chem. 277 2002 22123 22130
11. Y. Dong, Q.Q. Qiu, J. Debear, W.F. Lathrop, D.R. Bertolini, and P.P. Tamburini 17β-Hydroxysteroid dehydrogenases in human bone cells J. Bone Miner. Res. 13 1998 1539 1546 (Pubitemid 28465294)
12. A. Purohit, A.M. Flanagan, and M.J. Reed Estrogen synthesis by osteoblast cell lines Endocrinology 131 1992 2027 2029
13. B.C. van der Eerden, C.W. Lowik, J.M. Wit, and M. Karperien Expression of estrogen receptors and enzymes involved in sex steroid metabolism in the rat tibia during sexual maturation J. Endocrinol. 180 2004 457 467 (Pubitemid 38443398)
14. D. Poirier, P. Bydal, M.R. Tremblay, K.M. Sam, and V. Luu-The Inhibitors of type II 17β-hydroxysteroid dehydrogenase Mol. Cell. Endocrinol. 171 2001 119 128
15. P. Bydal, S. Auger, and D. Poirier Inhibition of type 2 17β-hydroxysteroid dehydrogenase by estradiol derivatives bearing a lactone on the D-ring: structure-activity relationships Steroids 69 2004 325 342 (Pubitemid 38803000)
16. J.H. Cook, J. Baryza, C. Brennan, D. Lowe, M. Wang, A. Redman, W.J. Scott, and J.E. Wood Disubstituted cis-pyrrolidinones as inhibitors of 17b-hydroxysteroid dehydrogenase II. Part 1: synthetic approach Tetrahedron Lett. 46 2005 1525 1528 (Pubitemid 40215058)
17. D. Gunn, C. Akuche, J. Baryza, M.L. Blue, C. Brennan, A.M. Campbell, S. Choi, J. Cook, P. Conrad, B. Dixon, J. Dumas, P. Ehrlich, T. Gane, T. Joe, J. Johnson, J. Jordan, R. Kramss, P. Liu, J. Levy, D. Lowe, I. McAlexander, R. Natero, A.M. Redman, W. Scott, T. Seng, R. Sibley, M. Wang, Y. Wang, J. Wood, and Z. Zhang 4,5-Disubstituted cis-pyrrolidinones as inhibitors of type II 17β-hydroxysteroid dehydrogenase. Part 2. SAR Bioorg. Med. Chem. Lett. 15 2005 3053 3057 (Pubitemid 40755196)
18. J. Wood, C.M. Bagi, C. Akuche, A. Bacchiocchi, J. Baryza, M.L. Blue, C. Brennan, A.M. Campbell, S. Choi, J.H. Cook, P. Conrad, B.R. Dixon, P.P. Ehrlich, T. Gane, D. Gunn, T. Joe, J.S. Johnson, J. Jordan, R. Kramss, P. Liu, J. Levy, D.B. Lowe, I. McAlexander, R. Natero, A.M. Redman, W.J. Scott, C. Town, M. Wang, Y. Wang, and Z. Zhang 4,5-Disubstituted cis-pyrrolidinones as inhibitors of type II 17β-hydroxysteroid dehydrogenase. Part 3. Identification of lead candidate Bioorg. Med. Chem. Lett. 16 2006 4965 4968 (Pubitemid 44175841)
19. F. Picard, E. Baston, W. Reichert, and R.W. Hartmann Synthesis of N-substituted piperidine-4-(benzylidene-4-carboxylic acids) and evaluation as inhibitors of steroid-5alpha-reductase type 1 and 2 Bioorg. Med. Chem. 8 2000 1479 1487 (Pubitemid 30398467)
20. M.P. Lézé, M. Le Borgne, P. Pinson, A. Palusczak, M. Duflos, G. Le Baut, and R.W. Hartmann Synthesis and biological evaluation of 5-[(aryl)(1H-imidazol-1-yl)methyl]-1H-indoles: potent and selective aromatase inhibitors Bioorg. Med. Chem. Lett. 16 2006 1134 1137 (Pubitemid 43142977)
21. S. Gobbi, A. Cavalli, M. Negri, K.E. Schewe, F. Belluti, L. Piazzi, R.W. Hartmann, M. Recanatini, and A. Bisi Imidazolylmethylbenzophenones as highly potent aromatase inhibitors J. Med. Chem. 50 2007 3420 3422 (Pubitemid 47195449)
22. F. Leonetti, A. Favia, A. Rao, R. Aliano, A. Paluszcak, R.W. Hartmann, and A. Carotti Design, synthesis, and 3D QSAR of novel potent and selective aromatase inhibitors J. Med. Chem. 47 2004 6792 6803 (Pubitemid 40053767)
23. A. Stefanachi, A.D. Favia, O. Nicolotti, F. Leonetti, L. Pisani, M. Catto, C. Zimmer, R.W. Hartmann, and A. Carotti Design, synthesis, and biological evaluation of imidazolyl derivatives of 4,7-disubstituted coumarins as aromatase inhibitors selective over 17-alpha-hydroxylase/C17-20 lyase J. Med. Chem. 54 2011 1613 1625
24. Q. Hu, M. Negri, K. Jahn-Hoffmann, Y. Zhuang, S. Olgen, M. Bartels, U. Müller-Vieira, T. Lauterbach, and R.W. Hartmann Synthesis, biological evaluation, and molecular modeling studies of methylene imidazole substituted biaryls as inhibitors of human 17alpha-hydroxylase-17,20-lyase (CYP17)-part II: core rigidification and influence of substituents at the methylene bridge Bioorg. Med. Chem. 16 2008 7715 7727
25. U.E. Hille, Q. Hu, C. Vock, M. Negri, M. Bartels, U. Müller-Vieira, T. Lauterbach, and R.W. Hartmann Novel CYP17 inhibitors: synthesis, biological evaluation, structure-activity relationships and modelling of methoxy- and hydroxy-substituted methyleneimidazolyl biphenyls Eur. J. Med. Chem. 44 2009 2765 2775
26. M. Voets, I. Antes, C. Scherer, U. Müller-Vieira, K. Biemel, S. Marchais-Oberwinkler, and R.W. Hartmann 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. 49 2006 2222 2231
27. S. Lucas, R. Heim, M. Negri, I. Antes, C. Ries, K.E. Schewe, A. Bisi, S. Gobbi, and R.W. Hartmann Novel aldosterone synthase inhibitors with extended carbocyclic skeleton by a combined ligand-based and structure-based drug design approach J. Med. Chem. 51 2008 6138 6149
28. S. Lucas, R. Heim, C. Ries, K.E. Schewe, B. Birk, and R.W. Hartmann 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. 51 2008 8077 8087
29. R. Heim, S. Lucas, C.M. Grombein, C. Ries, K.E. Schewe, M. Negri, U. Müller-Vieira, B. Birk, and R.W. Hartmann Overcoming undesirable CYP1A2 inhibition of pyridylnaphthalene-type aldosterone synthase inhibitors: influence of heteroaryl derivatization on potency and selectivity J. Med. Chem. 51 2008 5064 5074
30. U.E. Hille, C. Zimmer, J. Haupenthal, and R.W. Hartmann Optimization of the first selective steroid-11β-hydroxylase (CYP11B1) inhibitors for the treatment of cortisol dependent diseases Med. Chem. Lett. 2 2011 559 564
31. U.E. Hille, C. Zimmer, C. Vock, and R.W. Hartmann First selective CYP11B inhibitors for the treatment of cortisol dependent diseases ACS Med. Chem. Lett. 2 2011 2 6
32. S. Marchais-Oberwinkler, M. Wetzel, E. Ziegler, P. Kruchten, R. Werth, C. Henn, R.W. Hartmann, and M. Frotscher New drug-like hydroxyphenylnaphthol steroidomimetics as potent and selective 17β-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of estrogen-dependent diseases J. Med. Chem. 54 2011 534 547
33. A. Oster, T. Klein, C. Henn, R. Werth, S. Marchais-Oberwinkler, M. Frotscher, and R.W. Hartmann Bicyclic substituted hydroxyphenylmethanone type inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1): the role of the bicyclic moiety ChemMedChem 6 2011 476 487
34. A. Spadaro, M. Negri, S. Marchais-Oberwinkler, E. Bey, and M. Frotscher Hydroxybenzothiazoles as new nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) PLoS One 7 2012 e29252
35. C. Henn, A. Einspanier, S. Marchais-Oberwinkler, M. Frotscher, and R.W. Hartmann Lead optimization of 17β-HSD1 inhibitors of the (hydroxyphenyl)naphthol sulfonamide type for the treatment of endometriosis J. Med. Chem. 55 2012 3307 3318
36. E. Bey, S. Marchais-Oberwinkler, P. Kruchten, M. Frotscher, R. Werth, A. Oster, O. Algul, A. Neugebauer, and R.W. Hartmann 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. 16 2008 6423 6435 (Pubitemid 351783414)
37. E. Bey, S. Marchais-Oberwinkler, M. Negri, P. Kruchten, A. Oster, T. Klein, A. Spadaro, R. Werth, M. Frotscher, B. Birk, and R.W. Hartmann 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. 52 2009 6724 6743
38. M. Wetzel, S. Marchais-Oberwinkler, and R.W. Hartmann 17β-HSD2 inhibitors for the treatment of osteoporosis: identification of a promising scaffold Bioorg. Med. Chem. 19 2011 807 815
39. M. Wetzel, S. Marchais-Oberwinkler, E. Perspicace, G. Möller, J. Adamski, and R.W. Hartmann Introduction of an electron withdrawing group on the hydroxyphenylnaphthol scaffold improves the potency of 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) inhibitors J. Med. Chem. 54 2011 7547 7557
40. K. Xu, Y.A. Al-Soud, M. Wetzel, R.W. Hartmann, and S. Marchais-Oberwinkler Triazole ring-opening leads to the discovery of potent nonsteroidal 17β-hydroxysteroid dehydrogenase type 2 inhibitors Eur. J. Med. Chem. 46 2011 5978 5990
41. K. Xu, M. Wetzel, R.W. Hartmann, and S. Marchais-Oberwinkler Synthesis and biological evaluation of spiro-δ-lactones as inhibitors of 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) Lett. Drug Des. Discov. 8 2011 406 421
42. M. Wetzel, E.M. Gargano, S. Hinsberger, S. Marchais-Oberwinkler, and R.W. Hartmann Discovery of a new class of bicyclic substituted hydroxyphenylmethanones as 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) inhibitors for the treatment of osteoporosis Eur. J. Med. Chem. 47 2012 1 17
43. Y.A. Al-Soud, S. Marchais-Oberwinkler, M. Frotscher, and R.W. Hartmann Synthesis and biological evaluation of phenyl substituted 1H-1,2,4-triazoles as non-steroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 2 Arch. Pharm. (Weinheim) 345 2012 610 621
44. S. Marchais-Oberwinkler, K. Xu, M. Wetzel, E. Perspicace, M. Negri, A. Meyer, A. Odermatt, G. Möller, J. Adamski, and R.W. Hartmann Structural optimization of 2,5-thiophene amides as highly potent and selective 17β-hydroxysteroid dehydrogenase type 2 inhibitors for the treatment of osteoporosis J. Med. Chem. 56 2013 167 181
45. P. Kruchten, R. Werth, S. Marchais-Oberwinkler, M. Frotscher, and R.W. Hartmann Development of a biological screening system for the evaluation of highly active and selective 17β-HSD1-inhibitors as potential therapeutic agents Mol. Cell. Endocrinol. 301 2009 154 157
46. D.F. Veber, S.R. Johnson, H.Y. Cheng, B.R. Smith, K.W. Ward, and K.D. Kopple Molecular properties that influence the oral bioavailability of drug candidates J. Med. Chem. 45 2002 2615 2623 (Pubitemid 34595232)
47. C.A. Lipinski Lead- and drug-like compounds: the rule-of-five revolution Drug Discov. Today: Technologies 1 2004 337 341 (Pubitemid 40186335)
48. W. Qiu, R.L. Campbell, A. Gangloff, P. Dupuis, R.P. Boivin, M.R. Tremblay, D. Poirier, and S.X. Lin A concerted, rational design of type 1 17β-hydroxysteroid dehydrogenase inhibitors: estradiol-adenosine hybrids with high affinity FASEB J. 16 2002 1829 1831
49. B.T. Zhu, G.Z. Han, J.Y. Shim, Y. Wen, and X.R. Jiang Quantitative structure-activity relationship of various endogenous estrogen metabolites for human estrogen receptor alpha and beta subtypes: insights into the structural determinants favoring a differential subtype binding Endocrinology 147 2006 4132 4150 (Pubitemid 44274976)
50. K.M. Sam, S. Auger, V. Luu-The, and D. Poirier Steroidal spiro-gamma-lactones that inhibit 17β-hydroxysteroid dehydrogenase activity in human placental microsomes J. Med. Chem. 38 1995 4518 4528
51. K.M. Sam, R.P. Boivin, M.R. Tremblay, S. Auger, and D. Poirier C16 and C17 derivatives of estradiol as inhibitors of 17β-hydroxysteroid dehydrogenase type 1: chemical synthesis and structure-activity relationships Drug Des. Discov. 15 1998 157 180 (Pubitemid 28301999)
52. H.K. Lin, J.M. Jez, B.P. Schlegel, D.M. Peehl, J.A. Pachter, and T.M. Penning Expression and characterization of recombinant type 2 3 alpha-hydroxysteroid dehydrogenase (HSD) from human prostate: demonstration of bifunctional 3 alpha/17β-HSD activity and cellular distribution Mol. Endocrinol. 11 1997 1971 1984 (Pubitemid 27524880)