Recent Progress in the Discovery of Next Generation Inhibitors of Aromatase from the Structure-Function Perspective

Journal of Medicinal Chemistry

Volumn 59, Issue 11, 2016, Pages 5131-5148

  Ghosh, Debashis ^a   Lo, Jessica ^a   Egbuta, Chinaza ^a  

^a SUNY UPSTATE MEDICAL UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINOGLUTETHIMIDE; ANASTROZOLE; AROMATASE; AROMATASE INHIBITOR; CASIMIROIN; COUMARIN DERIVATIVE; EXEMESTANE; FADROZOLE; FLAVONE DERIVATIVE; FORMESTANE; HALIDE; IMIDAZOLE DERIVATIVE; INDOLE DERIVATIVE; LETROZOLE; NATURAL PRODUCT; PYRROLE DERIVATIVE; QUINOLINE DERIVATIVE; SELECTIVE ESTROGEN RECEPTOR MODULATOR; SULFONAMIDE; TAMOXIFEN; TRITERPENOID; UNCLASSIFIED DRUG; VOROZOLE; XANTHONE DERIVATIVE;

AMBIGUITY; ANTIPROLIFERATIVE ACTIVITY; BINDING SITE; CATALYST; CRYSTAL STRUCTURE; DRUG DESIGN; ENZYME ACTIVE SITE; ENZYME SPECIFICITY; ENZYME STRUCTURE; HUMAN; IC50; KNOWLEDGE BASE; MEMBRANE; METABOLITE; MOLECULAR DOCKING; MOLECULAR DYNAMICS; PLACENTA; PROTEIN FUNCTION; REACTION ANALYSIS; REVIEW; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY; CHEMICAL STRUCTURE; CHEMISTRY; DRUG DEVELOPMENT; DRUG EFFECTS; METABOLISM; MOLECULAR MODEL;

AROMATASE; AROMATASE INHIBITORS; CATALYTIC DOMAIN; DRUG DISCOVERY; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84974529287     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b01281     Document Type: Review

References (182)

1. Santen, R. J.; Brodie, H.; Simpson, E. R.; Siiteri, P. K.; Brodie, A. History of Aromatase: Saga of an Important Biological Mediator and Therapeutic Target Endocr. Rev. 2009, 30, 343-375 10.1210/er.2008-0016
2. Simpson, E.; Jones, M.; Misso, M.; Hewitt, K.; Hill, R.; Maffei, L.; Carani, C.; Boon, W. C. Estrogen, a Fundamental Player in Energy Homeostasis J. Steroid Biochem. Mol. Biol. 2005, 95, 3-8 10.1016/j.jsbmb.2005.04.018
3. Ryan, K. J. Biological Aromatization of Steroids J. Biol. Chem. 1959, 234, 268-272
4. Smith, I. E.; Dowsett, M. Aromatase Inhibitors in Breast Cancer N. Engl. J. Med. 2003, 348, 2431-2442 10.1056/NEJMra023246
5. Buzdar, A. U.; Robertson, J. F.; Eiermann, W.; Nabholtz, J. M. An Overview of the Pharmacology and Pharmacokinetics of the Newer Generation Aromatase Inhibitors Anastrozole, Letrozole, and Exemestane Cancer 2002, 95, 2006-2016 10.1002/cncr.10908
6. Ghosh, D.; Griswold, J.; Erman, M.; Pangborn, W. Structural Basis for Androgen Specificity and Oestrogen Synthesis in Human Aromatase Nature 2009, 457, 219-223 10.1038/nature07614
7. Szklarz, G. D.; Halpert, J. R. Use of Homology Modeling in Conjunction with Site-Directed Mutagenesis for Analysis of Structure-Function Relationships of Mammalian Cytochromes P450 Life Sci. 1997, 61, 2507-2520 10.1016/S0024-3205(97)00717-0
8. Laughton, C. A.; Zvelbil, M. J.; Neidle, S. A Detailed Molecular Model for Human Aromatase J. Steroid Biochem. Mol. Biol. 1993, 44, 399-407 10.1016/0960-0760(93)90243-P
9. Favia, A. D.; Cavalli, A.; Masetti, M.; Carotti, A.; Recanatini, M. Three-Dimensional Model of the Human Aromatase Enzyme and Density Functional Parameterization of the Iron-Containing Protoporphyrin IX for a Molecular Dynamics Study of Heme-Cysteinato Cytochromes Proteins: Struct., Funct., Genet. 2006, 62, 1074-1087 10.1002/prot.20829
10. Karkola, S.; Holtje, H. D.; Wahala, K. A Three-Dimensional Model of CYP19 Aromatase for Structure-Based Drug Design J. Steroid Biochem. Mol. Biol. 2007, 105, 63-70 10.1016/j.jsbmb.2006.11.023
11. Graham-Lorence, S.; Amarneh, B.; White, R. E.; Peterson, J. A.; Simpson, E. R. A Three-Dimensional Model of Aromatase Cytochrome P450 Protein Sci. 1995, 4, 1065-1080 10.1002/pro.5560040605
12. Lala, P.; Higashiyama, T.; Erman, M.; Griswold, J.; Wagner, T.; Osawa, Y.; Ghosh, D. Suppression of Human Cytochrome P450 Aromatase Activity by Monoclonal and Recombinant Antibody Fragments and Identification of a Stable Antigenic Complex J. Steroid Biochem. Mol. Biol. 2004, 88, 235-245 10.1016/j.jsbmb.2003.12.010
13. Ghosh, D.; Griswold, J.; Erman, M.; Pangborn, W. X-Ray Structure of Human Aromatase Reveals an Androgen-Specific Active Site J. Steroid Biochem. Mol. Biol. 2010, 118, 197-202 10.1016/j.jsbmb.2009.09.012
14. Lo, J.; Di Nardo, G.; Griswold, J.; Egbuta, C.; Jiang, W.; Gilardi, G.; Ghosh, D. Structural Basis for the Functional Roles of Critical Residues in Human Cytochrome P450 Aromatase Biochemistry 2013, 52, 5821-5829 10.1021/bi400669h
15. Waterman, M. R. Anticancer Drug Target Pictured Nature 2009, 457, 159-160 10.1038/457159a
16. Favia, A. D.; Nicolotti, O.; Stefanachi, A.; Leonetti, F.; Carotti, A. Computational Methods for the Design of Potent Aromatase Inhibitors Expert Opin. Drug Discovery 2013, 8, 395-409 10.1517/17460441.2013.768983
17. Di Nardo, G.; Breitner, M.; Bandino, A.; Ghosh, D.; Jennings, G. K.; Hackett, J. C.; Gilardi, G. Evidence for an Elevated Aspartate pKa in the Active Site of Human Aromatase J. Biol. Chem. 2015, 290, 1186-1196 10.1074/jbc.M114.595108
18. Sen, K.; Hackett, J. C. Coupled Electron Transfer and Proton Hopping in the Final Step of CYP19-Catalyzed Androgen Aromatization Biochemistry 2012, 51, 3039-3049 10.1021/bi300017p
19. Lipton, A.; Santen, R. J. Proceedings: Medical Adrenalectomy Using Aminoglutethimide and Dexamethasone in Advanced Breast Cancer Cancer 1974, 33, 503-512 10.1002/1097-0142(197402)33:2<503::AID-CNCR2820330227>3.0.CO;2-L
20. di Salle, E.; Ornati, G.; Giudici, D.; Lassus, M.; Evans, T. R.; Coombes, R. C. Exemestane (FCE 24304), a New Steroidal Aromatase Inhibitor J. Steroid Biochem. Mol. Biol. 1992, 43, 137-143 10.1016/0960-0760(92)90198-R
21. Dexter, R. N.; Fishman, L. M.; Ney, R. L.; Liddle, G. W. Inhibition of Adrenal Corticosteroid Synthesis by Aminoglutethimide: Studies of the Mechanism of Action J. Clin. Endocrinol. Metab. 1967, 27, 473-480 10.1210/jcem-27-4-473
22. Pittman, J. A.; Brown, R. W. Antithyroid and Antiadrenocortical Activity of Aminoglutethimide J. Clin. Endocrinol. Metab. 1966, 26, 1014-1016 10.1210/jcem-26-9-1014
23. Häusler, A.; Schenkel, L.; Krähenbühl, C.; Monnet, G.; Bhatnagar, A. An in Vitro Method to Determine the Selective Inhibition of Estrogen Biosynthesis by Aromatase Inhibitors J. Steroid Biochem. 1989, 33, 125-131 10.1016/0022-4731(89)90367-1
24. Dowsett, M.; Santner, S. J.; Santen, R. J.; Jeffcoate, S. L.; Smith, I. E. Effective Inhibition by Low Dose Aminoglutethimide of Peripheral Aromatization in Postmenopausal Breast Cancer Patients Br. J. Cancer 1985, 52, 31-35 10.1038/bjc.1985.144
25. Santen, R.; Santner, S.; Davis, B.; Veldhuis, J.; Samojlik, E.; Ruby, E. Aminoglutethimide Inhibits Extraglandular Estrogen Production in Postmenopausal Women with Breast Carcinoma∗ J. Clin. Endocrinol. Metab. 1978, 47, 1257-1265 10.1210/jcem-47-6-1257
26. Burnett, R. D.; Kirk, D. N. Some Observations on the Preparation of 2-Hydroxy-Steroid 4-En-3 Ones J. Chem. Soc., Perkin Trans. 1 1973, 17, 1830-1836 10.1039/p19730001830
27. Coombes, R. C.; Goss, P.; Dowsett, M.; Gazet, J. C.; Brodie, A. 4-Hydroxyandrostenedione in Treatment of Postmenopausal Patients with Advanced Breast Cancer Lancet 1984, 324, 1237-1239 10.1016/S0140-6736(84)92795-8
28. Coombes, R. C.; Goss, P. E.; Dowsett, M.; Hutchinson, G.; Cunningham, D.; Jarman, M.; Brodie, A. M. 4-Hydroxyandrostenedione Treatment for Postmenopausal Patients with Advanced Breast Cancer Steroids 1987, 50, 245-252 10.1016/0039-128X(83)90075-2
29. Dowsett, M.; Cunningham, D. C.; Stein, R. C.; Evans, S.; Dehennin, L.; Hedley, A.; Coombes, R. C. Dose-Related Endocrine Effects and Pharmacokinetics of Oral and Intramuscular 4-Hydroxyandrostenedione in Postmenopausal Breast Cancer Patients Cancer Res. 1989, 49, 1306-1312 10.1016/0378-5122(89)90231-4
30. Stein, R. C.; Dowsett, M.; Hedley, A.; Davenport, J.; Gazet, J. C.; Ford, H. T.; Coombes, R. C. Treatment of Advanced Breast Cancer in Postmenopausal Women with 4-Hydroxyandrostenedione Cancer Chemother. Pharmacol. 1990, 26, 75-78 10.1007/BF02940300
31. Stein, R. C.; Dowsett, M.; Hedley, A.; Gazet, J. C.; Ford, H. T.; Coombes, R. C. The Clinical and Endocrine Effects of 4-Hydroxyandrostenedione Alone and in Combination with Goserelin in Premenopausal Women with Advanced Breast Cancer Br. J. Cancer 1990, 62, 679-683 10.1038/bjc.1990.356
32. Brodie, A. M.; Marsh, D. A.; Wu, J. T.; Brodie, H. J. Aromatase Inhibitors and Their Use in Controlling Oestrogen-Dependent Processes J. Steroid Biochem. 1979, 11, 107-112 10.1016/0022-4731(79)90283-8
33. Di Salle, E.; Briatico, G.; Giudici, D.; Ornati, G.; Zaccheo, T.; Buzzetti, F.; Nesi, M.; Panzeri, A. Novel Aromatase and 5 Alpha-Reductase Inhibitors J. Steroid Biochem. Mol. Biol. 1994, 49, 289-294 10.1016/0960-0760(94)90270-4
34. Santen, R.; Langecker, P.; Santner, S.; Sikka, S.; Rajfer, J.; Swerdloff, R. Potency and Specificity of CGS-16949A as an Aromatase Inhibitor Endocr. Res. 1990, 16, 77-91 10.1080/07435809009035921
35. Browne, L. J.; Gude, C.; Rodriguez, H.; Steele, R. E.; Bhatnager, A. Fadrozole Hydrochloride: A Potent, Selective, Nonsteroidal Inhibitor of Aromatase for the Treatment of Estrogen-Dependent Disease J. Med. Chem. 1991, 34, 725-736 10.1021/jm00106a038
36. Bossche, H. V.; Moereels, H.; Koymans, L. M. Aromatase Inhibitors-Mechanisms for Non-Steroidal Inhibitors Breast Cancer Res. Treat. 1994, 30, 43-55 10.1007/BF00682740
37. Santen, R. J.; Demers, L. M.; Adlercreutz, H.; Harvey, H.; Santner, S.; Sanders, S.; Lipton, A. Inhibition of Aromatase with CGS 16949A in Postmenopausal Women J. Clin. Endocrinol. Metab. 1989, 68, 99-106 10.1210/jcem-68-1-99
38. Lipton, A.; Harvey, H. A.; Demers, L. M.; Hanagan, J. R.; Mulagha, M. T.; Kochak, G. M.; Fitzsimmons, S.; Sanders, S. I.; Santen, R. J. A Phase I Trial of CGS 16949A. A New Aromatase Inhibitor Cancer 1990, 65, 1279-1285 10.1002/1097-0142(19900315)65:6<1279::AID-CNCR2820650604>3.0.CO;2-3
39. Dowsett, M.; Stein, R. C.; Mehta, A.; Coombes, R. C. Potency and Selectivity of the Non-Steroidal Aromatase Inhibitor CGS 16949A in Postmenopausal Breast Cancer Patients Clin. Endocrinol. 1990, 32, 623-634 10.1111/j.1365-2265.1990.tb00906.x
40. Stein, R. C.; Dowsett, M.; Davenport, J.; Hedley, A.; Ford, H. T.; Gazet, J. C.; Coombes, R. C. Preliminary Study of the Treatment of Advanced Breast Cancer in Postmenopausal Women with the Aromatase Inhibitor CGS 16949A Cancer Res. 1990, 50, 1381-1384
41. Santen, R. J.; Demers, L. M.; Lynch, J.; Harvey, H.; Lipton, A.; Mulagha, M.; Hanagan, J.; Garber, J. E.; Henderson, I. C.; Navari, R. M. et al. Specificity of Low Dose Fadrozole Hydrochloride (CGS 16949A) as an Aromatase Inhibitor J. Clin. Endocrinol. Metab. 1991, 73, 99-106 10.1210/jcem-73-1-99
42. Raats, J. I.; Falkson, G.; Falkson, H. C. A Study of Fadrozole, a New Aromatase Inhibitor, in Postmenopausal Women with Advanced Metastatic Breast Cancer J. Clin. Oncol. 1992, 10, 111-116
43. Miller, W. R. Biology of Aromatase Inhibitors: Pharmacology/Endocrinology within the Breast Endocr.-Relat. Cancer 1999, 6, 187-195 10.1677/erc.0.0060187
44. Brodie, A. M.; Njar, V. C. Aromatase Inhibitors in Advanced Breast Cancer: Mechanism of Action and Clinical Implications J. Steroid Biochem. Mol. Biol. 1998, 66, 1-10 10.1016/S0960-0760(98)00022-3
45. Gibson, L. J.; Dawson, C.; Lawrence, D. H.; Bliss, J. M. Aromatase Inhibitors for Treatment of Advanced Breast Cancer in Postmenopausal Women Cochrane Database Syst. Rev. 2007, CD003370 10.1002/14651858.CD003370.pub2
46. Ghosh, D.; Lo, J.; Morton, D.; Valette, D.; Xi, J.; Griswold, J.; Hubbell, S.; Egbuta, C.; Jiang, W.; An, J.; Davies, H. M. Novel Aromatase Inhibitors by Structure-Guided Design J. Med. Chem. 2012, 55, 8464-8476 10.1021/jm300930n
47. Egbuta, C.; Lo, J.; Ghosh, D. Mechanism of Inhibition of Estrogen Biosynthesis by Azole Fungicides Endocrinology 2014, 155, 4622-4628 10.1210/en.2014-1561
48. Goss, P. E.; Ingle, J. N.; Pritchard, K. I.; Ellis, M. J.; Sledge, G. W.; Budd, G. T.; Rabaglio, M.; Ansari, R. H.; Johnson, D. B.; Tozer, R.; D'Souza, D. P.; Chalchal, H.; Spadafora, S.; Stearns, V.; Perez, E. A.; Liedke, P. E.; Lang, I.; Elliott, C.; Gelmon, K. A.; Chapman, J. A.; Shepherd, L. E. Exemestane Versus Anastrozole in Postmenopausal Women with Early Breast Cancer: NCIC CTG MA.27 - a Randomized Controlled Phase Iii Trial J. Clin. Oncol. 2013, 31, 1398-1404 10.1200/JCO.2012.44.7805
49. Murray, J.; Young, O. E.; Renshaw, L.; White, S.; Williams, L.; Evans, D. B.; Thomas, J. S.; Dowsett, M.; Dixon, J. M. A Randomised Study of the Effects of Letrozole and Anastrozole on Oestrogen Receptor Positive Breast Cancers in Postmenopausal Women Breast Cancer Res. Treat. 2009, 114, 495-501 10.1007/s10549-008-0027-0
50. Zilembo, N.; Noberasco, C.; Bajetta, E.; Martinetti, A.; Mariani, L.; Orefice, S.; Buzzoni, R.; Di Bartolomeo, M.; Di Leo, A.; Laffranchi, A. et al. Endocrinological and Clinical Evaluation of Exemestane, a New Steroidal Aromatase Inhibitor Br. J. Cancer 1995, 72, 1007-1012 10.1038/bjc.1995.451
51. Johannessen, D. C.; Engan, T.; Di Salle, E.; Zurlo, M. G.; Paolini, J.; Ornati, G.; Piscitelli, G.; Kvinnsland, S.; Lonning, P. E. Endocrine and Clinical Effects of Exemestane (PNU155971), a Novel Steroidal Aromatase Inhibitor, in Postmenopausal Breast Cancer Patients: A Phase I Study Clin. Cancer Res. 1997, 3, 1101-1108
52. Lonning, P. E.; Paridaens, R.; Thurlimann, B.; Piscitelli, G.; di Salle, E. Exemestane Experience in Breast Cancer Treatment J. Steroid Biochem. Mol. Biol. 1997, 61, 151-155 10.1016/S0960-0760(97)80007-6
53. Thurlimann, B.; Paridaens, R.; Serin, D.; Bonneterre, J.; Roche, H.; Murray, R.; di Salle, E.; Lanzalone, S.; Zurlo, M. G.; Piscitelli, G. Third-Line Hormonal Treatment with Exemestane in Postmenopausal Patients with Advanced Breast Cancer Progressing on Aminoglutethimide: A Phase II Multicentre Multinational Study. Exemestane Study Group Eur. J. Cancer 1997, 33, 1767-1773 10.1016/S0959-8049(97)00283-9
54. Geisler, J.; King, N.; Anker, G.; Ornati, G.; Di Salle, E.; Lonning, P. E.; Dowsett, M. In Vivo Inhibition of Aromatization by Exemestane, a Novel Irreversible Aromatase Inhibitor, in Postmenopausal Breast Cancer Patients Clin. Cancer Res. 1998, 4, 2089-2093
55. Lonning, P. E. Pharmacological Profiles of Exemestane and Formestane, Steroidal Aromatase Inhibitors Used for Treatment of Postmenopausal Breast Cancer Breast Cancer Res. Treat. 1998, 49 (Suppl. 1) S45-52 (discussion S73-47) 10.1023/A:1006048722559
56. Jones, S.; Vogel, C.; Arkhipov, A.; Fehrenbacher, L.; Eisenberg, P.; Cooper, B.; Honig, S.; Polli, A.; Whaley, F.; di Salle, E.; Tiffany, J.; Consonni, A.; Miller, L. Multicenter, Phase II Trial of Exemestane as Third-Line Hormonal Therapy of Postmenopausal Women with Metastatic Breast Cancer. Aromasin Study Group J. Clin. Oncol. 1999, 17, 3418-3425
57. Kaufmann, M.; Bajetta, E.; Dirix, L. Y.; Fein, L. E.; Jones, S. E.; Cervek, J.; Fowst, C.; Polli, A.; Di Salle, E.; Massimini, G.; Piscitelli, G. Exemestane Improves Survival Compared with Megoestrol Acetate in Postmenopausal Patients with Advanced Breast Cancer Who Have Failed on Tamoxifen. Results of a Double-Blind Randomised Phase III Trial Eur. J. Cancer 2000, 36 (Suppl. 4) S86-87 10.1016/S0959-8049(00)00240-9
58. Kaufmann, M.; Bajetta, E.; Dirix, L. Y.; Fein, L. E.; Jones, S. E.; Zilembo, N.; Dugardyn, J. L.; Nasurdi, C.; Mennel, R. G.; Cervek, J.; Fowst, C.; Polli, A.; di Salle, E.; Arkhipov, A.; Piscitelli, G.; Miller, L. L.; Massimini, G. Exemestane Improves Survival in Metastatic Breast Cancer: Results of a Phase III Randomized Study Clin. Breast Cancer 2000, 1 (Suppl. 1) S15-18 10.3816/CBC.2000.s.003
59. Kaufmann, M.; Bajetta, E.; Dirix, L. Y.; Fein, L. E.; Jones, S. E.; Zilembo, N.; Dugardyn, J. L.; Nasurdi, C.; Mennel, R. G.; Cervek, J.; Fowst, C.; Polli, A.; di Salle, E.; Arkhipov, A.; Piscitelli, G.; Miller, L. L.; Massimini, G. Exemestane Is Superior to Megestrol Acetate after Tamoxifen Failure in Postmenopausal Women with Advanced Breast Cancer: Results of a Phase Iii Randomized Double-Blind Trial. The Exemestane Study Group J. Clin. Oncol. 2000, 18, 1399-1411
60. Plourde, P. V.; Dyroff, M.; Dukes, M. Arimidex: A Potent and Selective Fourth-Generation Aromatase Inhibitor Breast Cancer Res. Treat. 1994, 30, 103-111 10.1007/BF00682745
61. Dukes, M.; Edwards, P. N.; Large, M.; Smith, I. K.; Boyle, T. The Preclinical Pharmacology of "Arimidex" (Anastrozole; ZD1033) - a Potent, Selective Aromatase Inhibitor J. Steroid Biochem. Mol. Biol. 1996, 58, 439-445 10.1016/0960-0760(96)00064-7
62. Buzdar, A. U.; Jonat, W.; Howell, A.; Jones, S. E.; Blomqvist, C. P.; Vogel, C. L.; Eiermann, W.; Wolter, J. M.; Steinberg, M.; Webster, A.; Lee, D. Anastrozole Versus Megestrol Acetate in the Treatment of Postmenopausal Women with Advanced Breast Carcinoma: Results of a Survival Update Based on a Combined Analysis of Data from Two Mature Phase III Trials. Arimidex Study Group Cancer 1998, 83, 1142-1152 10.1002/(SICI)1097-0142(19980915)83:6<1142::AID-CNCR13>3.0.CO;2-5
63. Yates, R. A.; Dowsett, M.; Fisher, G. V.; Selen, A.; Wyld, P. J. Arimidex (ZD1033): A Selective, Potent Inhibitor of Aromatase in Postmenopausal Female Volunteers Br. J. Cancer 1996, 73, 543-548 10.1038/bjc.1996.94
64. Buzdar, A. U.; Jones, S. E.; Vogel, C. L.; Wolter, J.; Plourde, P.; Webster, A. A Phase III Trial Comparing Anastrozole (1 and 10 Milligrams), a Potent and Selective Aromatase Inhibitor, with Megestrol Acetate in Postmenopausal Women with Advanced Breast Carcinoma. Arimidex Study Group Cancer 1997, 79, 730-739 10.1002/(SICI)1097-0142(19970215)79:4<730::AID-CNCR10>3.0.CO;2-0
65. Buzdar, A.; Douma, J.; Davidson, N.; Elledge, R.; Morgan, M.; Smith, R.; Porter, L.; Nabholtz, J.; Xiang, X.; Brady, C. Phase III, Multicenter, Double-Blind, Randomized Study of Letrozole, an Aromatase Inhibitor, for Advanced Breast Cancer Versus Megestrol Acetate J. Clin. Oncol. 2001, 19, 3357-3366
66. Cohen, M. H.; Johnson, J. R.; Li, N.; Chen, G.; Pazdur, R. Approval Summary: Letrozole in the Treatment of Postmenopausal Women with Advanced Breast Cancer Clin. Cancer Res. 2002, 8, 665-669
67. Goss, P. E.; Ingle, J. N.; Martino, S.; Robert, N. J.; Muss, H. B.; Piccart, M. J.; Castiglione, M.; Tu, D.; Shepherd, L. E.; Pritchard, K. I.; Livingston, R. B.; Davidson, N. E.; Norton, L.; Perez, E. A.; Abrams, J. S.; Cameron, D. A.; Palmer, M. J.; Pater, J. L. Randomized Trial of Letrozole Following Tamoxifen as Extended Adjuvant Therapy in Receptor-Positive Breast Cancer: Updated Findings from NCIC CTG MA.17 J. Natl. Cancer Inst. 2005, 97, 1262-1271 10.1093/jnci/dji250
68. Goss, P. E.; Ingle, J. N.; Martino, S.; Robert, N. J.; Muss, H. B.; Piccart, M. J.; Castiglione, M.; Tu, D.; Shepherd, L. E.; Pritchard, K. I.; Livingston, R. B.; Davidson, N. E.; Norton, L.; Perez, E. A.; Abrams, J. S.; Therasse, P.; Palmer, M. J.; Pater, J. L. A Randomized Trial of Letrozole in Postmenopausal Women after Five Years of Tamoxifen Therapy for Early-Stage Breast Cancer N. Engl. J. Med. 2003, 349, 1793-1802 10.1056/NEJMoa032312
69. Lipton, A.; Leitzel, K.; Ali, S. M.; Demers, L.; Harvey, H. A.; Chaudri-Ross, H. A.; Evans, D.; Lang, R.; Hackl, W.; Hamer, P.; Carney, W. Serum HER-2/Neu Conversion to Positive at the Time of Disease Progression in Patients with Breast Carcinoma on Hormone Therapy Cancer 2005, 104, 257-263 10.1002/cncr.21202
70. Meng, S.; Tripathy, D.; Shete, S.; Ashfaq, R.; Haley, B.; Perkins, S.; Beitsch, P.; Khan, A.; Euhus, D.; Osborne, C.; Frenkel, E.; Hoover, S.; Leitch, M.; Clifford, E.; Vitetta, E.; Morrison, L.; Herlyn, D.; Terstappen, L. W.; Fleming, T.; Fehm, T.; Tucker, T.; Lane, N.; Wang, J.; Uhr, J. HER-2 Gene Amplification Can Be Acquired as Breast Cancer Progresses Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 9393-9398 10.1073/pnas.0402993101
71. Hu, J. C.; Mokbel, K. Does C-Erbb2/HER2 Overexpression Predict Adjuvant Tamoxifen Failure in Patients with Early Breast Cancer? European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 2001, 27, 335-337 10.1053/ejso.2000.1078
72. Osborne, C. K.; Bardou, V.; Hopp, T. A.; Chamness, G. C.; Hilsenbeck, S. G.; Fuqua, S. A.; Wong, J.; Allred, D. C.; Clark, G. M.; Schiff, R. Role of the Estrogen Receptor Coactivator AIB1 (Src-3) and HER-2/Neu in Tamoxifen Resistance in Breast Cancer J. Natl. Cancer Inst. 2003, 95, 353-361 10.1093/jnci/95.5.353
73. Liehr, J. G. Is Estradiol a Genotoxic Mutagenic Carcinogen? Endocr. Rev. 2000, 21, 40-54 10.1210/edrv.21.1.0386
74. Breast International Group 1-98 Collaborative Group; Thurlimann, B.; Keshaviah, A.; Coates, A. S.; Mouridsen, H.; Mauriac, L.; Forbes, J. F.; Paridaens, R.; Castiglione-Gertsch, M.; Gelber, R. D.; Rabaglio, M.; Smith, I.; Wardley, A.; Price, K. N.; Goldhirsch, A. Comparison of Letrozole and Tamoxifen in Postmenopausal Women with Early Breast Cancer N. Engl. J. Med. 2005, 353, 2747-2757 10.1056/NEJMoa052258
75. Goss, P. E. Pre-Clinical and Clinical Review of Vorozole, a New Third Generation Aromatase Inhibitor Breast Cancer Res. Treat. 1998, 49 (Suppl. 1) S59-65 (discussion S73-57) 10.1023/A:1006052923468
76. Goss, P. E.; Winer, E. P.; Tannock, I. F.; Schwartz, L. H. Randomized Phase III Trial Comparing the New Potent and Selective Third-Generation Aromatase Inhibitor Vorozole with Megestrol Acetate in Postmenopausal Advanced Breast Cancer Patients. North American Vorozole Study Group J. Clin. Oncol. 1999, 17, 52-63
77. Williams, P. A.; Cosme, J.; Vinkovic, D. M.; Ward, A.; Angove, H. C.; Day, P. J.; Vonrhein, C.; Tickle, I. J.; Jhoti, H. Crystal Structures of Human Cytochrome P450 3A4 Bound to Metyrapone and Progesterone Science 2004, 305, 683-686 10.1126/science.1099736
78. Rowland, P.; Blaney, F. E.; Smyth, M. G.; Jones, J. J.; Leydon, V. R.; Oxbrow, A. K.; Lewis, C. J.; Tennant, M. G.; Modi, S.; Eggleston, D. S.; Chenery, R. J.; Bridges, A. M. Crystal Structure of Human Cytochrome P450 2D6 J. Biol. Chem. 2006, 281, 7614-7622 10.1074/jbc.M511232200
79. 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 10.1210/me.2012-1287
80. DeVore, N. M.; Scott, E. E. Structures of Cytochrome P450 17A1 with Prostate Cancer Drugs Abiraterone and Tok-001 Nature 2012, 482, 116-119 10.1038/nature10743
81. Zhao, B.; Lei, L.; Kagawa, N.; Sundaramoorthy, M.; Banerjee, S.; Nagy, L. D.; Guengerich, F. P.; Waterman, M. R. Three-Dimensional Structure of Steroid 21-Hydroxylase (Cytochrome P450 21A2) with Two Substrates Reveals Locations of Disease-Associated Variants J. Biol. Chem. 2012, 287, 10613-10622 10.1074/jbc.M111.323501
82. Annalora, A. J.; Goodin, D. B.; Hong, W. X.; Zhang, Q.; Johnson, E. F.; Stout, C. D. Crystal Structure of CYP24A1, a Mitochondrial Cytochrome P450 Involved in Vitamin D Metabolism J. Mol. Biol. 2010, 396, 441-451 10.1016/j.jmb.2009.11.057
83. Strushkevich, N.; Usanov, S. A.; Park, H. W. Structural Basis of Human CYP51 Inhibition by Antifungal Azoles J. Mol. Biol. 2010, 397, 1067-1078 10.1016/j.jmb.2010.01.075
84. Bouchoucha, N.; Samara-Boustani, D.; Pandey, A. V.; Bony-Trifunovic, H.; Hofer, G.; Aigrain, Y.; Polak, M.; Fluck, C. E. Characterization of a Novel CYP19A1 (Aromatase) R192H Mutation Causing Virilization of a 46,XX Newborn, Undervirilization of the 46,XY Brother, but No Virilization of the Mother During Pregnancies Mol. Cell. Endocrinol. 2014, 390, 8-17 10.1016/j.mce.2014.03.008
85. Marino, R.; Perez Garrido, N.; Costanzo, M.; Guercio, G.; Juanes, M.; Rocco, C.; Ramirez, P.; Warman, D. M.; Ciaccio, M.; Pena, G. Five New Cases of 46, XX Aromatase Deficiency: Clinical Follow-up from Birth to Puberty, a Novel Mutation, and a Founder Effect J. Clin. Endocrinol. Metab. 2015, 100, E301-E307 10.1210/jc.2014-2967
86. Jiang, W.; Ghosh, D. Motion and Flexibility in Human Cytochrome P450 Aromatase PLoS One 2012, 7, e32565 10.1371/journal.pone.0032565
87. Akhtar, M.; Calder, M. R.; Corina, D. L.; Wright, J. N. Mechanistic Studies on C-19 Demethylation in Oestrogen Biosynthesis Biochem. J. 1982, 201, 569-580 10.1042/bj2010569
88. Akhtar, M.; Njar, V. C.; Wright, J. N. Mechanistic Studies on Aromatase and Related C-C Bond Cleaving P-450 Enzymes J. Steroid Biochem. Mol. Biol. 1993, 44, 375-387 10.1016/0960-0760(93)90241-N
89. Hackett, J. C.; Brueggemeier, R. W.; Hadad, C. M. The Final Catalytic Step of Cytochrome P450 Aromatase: A Density Functional Theory Study J. Am. Chem. Soc. 2005, 127, 5224-5237 10.1021/ja044716w
90. Akhtar, M.; Wright, J. N.; Lee-Robichaud, P. A Review of Mechanistic Studies on Aromatase (CYP19) and 17alpha-Hydroxylase-17,20-Lyase (CYP17) J. Steroid Biochem. Mol. Biol. 2011, 125, 2-12 10.1016/j.jsbmb.2010.11.003
91. Guallar, V.; Baik, M.-H.; Lippard, S. J.; Friesner, R. A. Peripheral Heme Substituents Control the Hydrogen-Atom Abstraction Chemistry in Cytochromes P450 Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 6998-7002 10.1073/pnas.0732000100
92. Gantt, S. L.; Denisov, I. G.; Grinkova, Y. V.; Sligar, S. G. The Critical Iron-Oxygen Intermediate in Human Aromatase Biochem. Biophys. Res. Commun. 2009, 387, 169-173 10.1016/j.bbrc.2009.06.154
93. Tosha, T.; Kagawa, N.; Ohta, T.; Yoshioka, S.; Waterman, M. R.; Kitagawa, T. Raman Evidence for Specific Substrate-Induced Structural Changes in the Heme Pocket of Human Cytochrome P450 Aromatase During the Three Consecutive Oxygen Activation Steps Biochemistry 2006, 45, 5631-5640 10.1021/bi060094a
94. Mak, P. J.; Luthra, A.; Sligar, S. G.; Kincaid, J. R. Resonance Raman Spectroscopy of the Oxygenated Intermediates of Human CYP19A1 Implicates a Compound I Intermediate in the Final Lyase Step J. Am. Chem. Soc. 2014, 136, 4825-4828 10.1021/ja500054c
95. Khatri, Y.; Luthra, A.; Duggal, R.; Sligar, S. G. Kinetic Solvent Isotope Effect in Steady-State Turnover by CYP19A1 Suggests Involvement of Compound 1 for Both Hydroxylation and Aromatization Steps FEBS Lett. 2014, 588, 3117-3122 10.1016/j.febslet.2014.06.050
96. Yoshimoto, F. K.; Guengerich, F. P. Mechanism of the Third Oxidative Step in the Conversion of Androgens to Estrogens by Cytochrome P450 19A1 Steroid Aromatase J. Am. Chem. Soc. 2014, 136, 15016-15025 10.1021/ja508185d
97. Ghosh, D.; Lo, J.; Egbuta, C. Structure, Function and Inhibition of Aromatase. In Resistance to Aromatase Inhibitors in Breast Cancer; Springer, 2015; pp 33-61.
98. Sasano, H.; Sato, S.; Ito, K.; Yajima, A.; Nakamura, J.; Yoshihama, M.; Ariga, K.; Anderson, T. J.; Miller, W. R. Effects of Aromatase Inhibitors on the Pathobiology of the Human Breast, Endometrial and Ovarian Carcinoma Endocr.-Relat. Cancer 1999, 6, 197-204 10.1677/erc.0.0060197
99. Pavone, M. E.; Bulun, S. E. Aromatase Inhibitors for the Treatment of Endometriosis Fertil. Steril. 2012, 98, 1370-1379 10.1016/j.fertnstert.2012.08.053
100. Li, Y. F.; Hu, W.; Fu, S. Q.; Li, J. D.; Liu, J. H.; Kavanagh, J. J. Aromatase Inhibitors in Ovarian Cancer: Is There a Role? International Gynecological Cancer Society 2008, 18, 600-614 10.1111/j.1525-1438.2007.01075.x
101. Weinberg, O. K.; Marquez-Garban, D. C.; Fishbein, M. C.; Goodglick, L.; Garban, H. J.; Dubinett, S. M.; Pietras, R. J. Aromatase Inhibitors in Human Lung Cancer Therapy Cancer Res. 2005, 65, 11287-11291 10.1158/0008-5472.CAN-05-2737
102. Brueggemeier, R. W. Aromatase, Aromatase Inhibitors, and Breast Cancer American Journal of Therapeutics. 2001, 8, 333-344 10.1097/00045391-200109000-00007
103. Brueggemeier, R. W.; Hackett, J. C.; Diaz-Cruz, E. S. Aromatase Inhibitors in the Treatment of Breast Cancer Endocr. Rev. 2005, 26, 331-345 10.1210/er.2004-0015
104. Brueggemeier, R. W. Update on the Use of Aromatase Inhibitors in Breast Cancer Expert Opin. Pharmacother. 2006, 7, 1919-1930 10.1517/14656566.7.14.1919
105. Grimm, S. W.; Dyroff, M. C. Inhibition of Human Drug Metabolizing Cytochromes P450 by Anastrozole, a Potent and Selective Inhibitor of Aromatase Drug Metab. Dispos. 1997, 25, 598-602
106. Miller, W. R.; Larionov, A. A. Understanding the Mechanisms of Aromatase Inhibitor Resistance Breast Cancer Res. 2012, 14, 201 10.1186/bcr2931
107. Kamdem, L. K.; Flockhart, D. A.; Desta, Z. In Vitro Cytochrome P450-Mediated Metabolism of Exemestane Drug Metab. Dispos. 2011, 39, 98-105 10.1124/dmd.110.032276
108. Femara (Letrozole) Prescribing Information. Novartis, East Hanover, NJ, 2014.
109. Ariazi, E. A.; Leitao, A.; Oprea, T. I.; Chen, B.; Louis, T.; Bertucci, A. M.; Sharma, C. G.; Gill, S. D.; Kim, H. R.; Shupp, H. A.; Pyle, J. R.; Madrack, A.; Donato, A. L.; Cheng, D.; Paige, J. R.; Jordan, V. C. Exemestane's 17-Hydroxylated Metabolite Exerts Biological Effects as an Androgen Mol. Cancer Ther. 2007, 6, 2817-2827 10.1158/1535-7163.MCT-07-0312
110. Masri, S.; Lui, K.; Phung, S.; Ye, J.; Zhou, D.; Wang, X.; Chen, S. Characterization of the Weak Estrogen Receptor Alpha Agonistic Activity of Exemestane Breast Cancer Res. Treat. 2009, 116, 461-470 10.1007/s10549-008-0151-x
111. Varela, C.; Tavares da Silva, E. J.; Amaral, C.; Correia da Silva, G.; Baptista, T.; Alcaro, S.; Costa, G.; Carvalho, R. A.; Teixeira, N. A.; Roleira, F. M. New Structure-Activity Relationships of A- and D-Ring Modified Steroidal Aromatase Inhibitors: Design, Synthesis, and Biochemical Evaluation J. Med. Chem. 2012, 55, 3992-4002 10.1021/jm300262w
112. Varela, C. L.; Amaral, C.; Correia-da-Silva, G.; Carvalho, R. A.; Teixeira, N. A.; Costa, S. C.; Roleira, F. M.; Tavares-da-Silva, E. J. Design, Synthesis and Biochemical Studies of New 7alpha-Allylandrostanes as Aromatase Inhibitors Steroids 2013, 78, 662-669 10.1016/j.steroids.2013.02.016
113. Bansal, R.; Guleria, S.; Thota, S.; Bodhankar, S. L.; Patwardhan, M. R.; Zimmer, C.; Hartmann, R. W.; Harvey, A. L. Design, Synthesis and Evaluation of Novel 16-Imidazolyl Substituted Steroidal Derivatives Possessing Potent Diversified Pharmacological Properties Steroids 2012, 77, 621-629 10.1016/j.steroids.2012.02.005
114. Yadav, M. R.; Sabale, P. M.; Giridhar, R.; Zimmer, C.; Haupenthal, J.; Hartmann, R. W. Synthesis of Some Novel Androstanes as Potential Aromatase Inhibitors Steroids 2011, 76, 464-470 10.1016/j.steroids.2010.12.013
115. Yadav, M. R.; Sabale, P. M.; Giridhar, R.; Zimmer, C.; Hartmann, R. W. Steroidal Carbonitriles as Potential Aromatase Inhibitors Steroids 2012, 77, 850-857 10.1016/j.steroids.2012.04.010
116. Ghosh, D.; Di Nardo, G.; Lo, J.; Jiang, W.; Griswold, J.; Gilardi, G. Ligand-Binding Interactions and Quaternary Association in Human Aromatase. 36th FEBS Congress, Torino, Italy; Perham, R., Ed.; Wiley-Blackwell, 2011; p 30.
117. Sgrignani, J.; Bon, M.; Colombo, G.; Magistrato, A. Computational Approaches Elucidate the Allosteric Mechanism of Human Aromatase Inhibition: A Novel Possible Route to Small-Molecule Regulation of Cyp450s Activities? J. Chem. Inf. Model. 2014, 54, 2856-2868 10.1021/ci500425y
118. Jiao, J.; Xiang, H.; Liao, Q. Recent Advancement in Nonsteroidal Aromatase Inhibitors for Treatment of Estrogen-Dependent Breast Cancer Curr. Med. Chem. 2010, 17, 3476-3487 10.2174/092986710792927877
119. 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 10.1021/jm301408t
120. Ferlin, M. G.; Carta, D.; Bortolozzi, R.; Ghodsi, R.; Chimento, A.; Pezzi, V.; Moro, S.; Hanke, N.; Hartmann, R. W.; Basso, G.; Viola, G. Design, Synthesis, and Structure-Activity Relationships of Azolylmethylpyrroloquinolines as Nonsteroidal Aromatase Inhibitors J. Med. Chem. 2013, 56, 7536-7551 10.1021/jm400377z
121. Ji, J. Z.; Lao, K. J.; Hu, J.; Pang, T.; Jiang, Z. Z.; Yuan, H. L.; Miao, J. S.; Chen, X.; Ning, S. S.; Xiang, H.; Guo, Y. M.; Yan, M.; Zhang, L. Y. Discovery of Novel Aromatase Inhibitors Using a Homogeneous Time-Resolved Fluorescence Assay Acta Pharmacol. Sin. 2014, 35, 1082-1092 10.1038/aps.2014.53
122. Bonfield, K.; Amato, E.; Bankemper, T.; Agard, H.; Steller, J.; Keeler, J. M.; Roy, D.; McCallum, A.; Paula, S.; Ma, L. Development of a New Class of Aromatase Inhibitors: Design, Synthesis and Inhibitory Activity of 3-Phenylchroman-4-One (Isoflavanone) Derivatives Bioorg. Med. Chem. 2012, 20, 2603-2613 10.1016/j.bmc.2012.02.042
123. Prachyawarakorn, V.; Sangpetsiripan, S.; Surawatanawong, P.; Mahidol, C.; Ruchirawat, S.; Kittakoop, P. Flavans from Desmos Cochinchinensis as Potent Aromatase Inhibitors MedChemComm 2013, 4, 1590-1596 10.1039/c3md00166k
124. Stefanachi, A.; Favia, A. D.; Nicolotti, O.; Leonetti, F.; Pisani, L.; Catto, M.; Zimmer, C.; Hartmann, R. W.; Carotti, A. 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. 2011, 54, 1613-1625 10.1021/jm101120u
125. Hong, Y.; Chen, S. Aromatase, Estrone Sulfatase, and 17beta-Hydroxysteroid Dehydrogenase: Structure-Function Studies and Inhibitor Development Mol. Cell. Endocrinol. 2011, 340, 120-126 10.1016/j.mce.2010.09.012
126. Woo, L. W.; Wood, P. M.; Bubert, C.; Thomas, M. P.; Purohit, A.; Potter, B. V. Synthesis and Structure-Activity Relationship Studies of Derivatives of the Dual Aromatase-Sulfatase Inhibitor 4-{[(4-Cyanophenyl)(4h-1,2,4-Triazol-4-Yl)Amino]Methyl}Phenyl Sulfamate ChemMedChem 2013, 8, 779-799 10.1002/cmdc.201300015
127. Wood, P. M.; Woo, L. W.; Labrosse, J. R.; Thomas, M. P.; Mahon, M. F.; Chander, S. K.; Purohit, A.; Reed, M. J.; Potter, B. V. Bicyclic Derivatives of the Potent Dual Aromatase-Steroid Sulfatase Inhibitor 2-Bromo-4-{[(4-Cyanophenyl)(4h-1,2,4-Triazol-4-Yl)Amino]Methyl}Phenylsulfamate: Synthesis, SAR, Crystal Structure, and in Vitro and in Vivo Activities ChemMedChem 2010, 5, 1577-1593 10.1002/cmdc.201000203
128. Woo, L. W.; Bubert, C.; Purohit, A.; Potter, B. V. Hybrid Dual Aromatase-Steroid Sulfatase Inhibitors with Exquisite Picomolar Inhibitory Activity ACS Med. Chem. Lett. 2011, 2, 243-247 10.1021/ml100273k
129. Woo, L. W.; Jackson, T.; Putey, A.; Cozier, G.; Leonard, P.; Acharya, K. R.; Chander, S. K.; Purohit, A.; Reed, M. J.; Potter, B. V. Highly Potent First Examples of Dual Aromatase-Steroid Sulfatase Inhibitors Based on a Biphenyl Template J. Med. Chem. 2010, 53, 2155-2170 10.1021/jm901705h
130. Wood, P. M.; Woo, L. W.; Thomas, M. P.; Mahon, M. F.; Purohit, A.; Potter, B. V. Aromatase and Dual Aromatase-Steroid Sulfatase Inhibitors from the Letrozole and Vorozole Templates ChemMedChem 2011, 6, 1423-1438 10.1002/cmdc.201100145
131. Lu, W. J.; Xu, C.; Pei, Z.; Mayhoub, A. S.; Cushman, M.; Flockhart, D. A. The Tamoxifen Metabolite Norendoxifen Is a Potent and Selective Inhibitor of Aromatase (CYP19) and a Potential Lead Compound for Novel Therapeutic Agents Breast Cancer Res. Treat. 2012, 133, 99-109 10.1007/s10549-011-1699-4
132. Lv, W.; Liu, J.; Lu, D.; Flockhart, D. A.; Cushman, M. Synthesis of Mixed (E,Z)-, (E)-, and (Z)-Norendoxifen with Dual Aromatase Inhibitory and Estrogen Receptor Modulatory Activities J. Med. Chem. 2013, 56, 4611-4618 10.1021/jm400364h
133. Pingaew, R.; Prachayasittikul, V.; Mandi, P.; Nantasenamat, C.; Prachayasittikul, S.; Ruchirawat, S.; Prachayasittikul, V. Synthesis and Molecular Docking of 1,2,3-Triazole-Based Sulfonamides as Aromatase Inhibitors Bioorg. Med. Chem. 2015, 23, 3472-3480 10.1016/j.bmc.2015.04.036
134. McNulty, J.; Nielsen, A. J.; Brown, C. E.; DiFrancesco, B. R.; Vurgun, N.; Nair, J. J.; Crankshaw, D. J.; Holloway, A. C. Investigation of Aryl Halides as Ketone Bioisosteres: Refinement of Potent and Selective Inhibitors of Human Cytochrome P450 19A1 (Aromatase) Bioorg. Med. Chem. Lett. 2013, 23, 6060-6063 10.1016/j.bmcl.2013.09.030
135. Wang, R.; Shi, H. F.; Zhao, J. F.; He, Y. P.; Zhang, H. B.; Liu, J. P. Design, Synthesis and Aromatase Inhibitory Activities of Novel Indole-Imidazole Derivatives Bioorg. Med. Chem. Lett. 2013, 23, 1760-1762 10.1016/j.bmcl.2013.01.045
136. Maiti, A.; Reddy, P. V.; Sturdy, M.; Marler, L.; Pegan, S. D.; Mesecar, A. D.; Pezzuto, J. M.; Cushman, M. Synthesis of Casimiroin and Optimization of Its Quinone Reductase 2 and Aromatase Inhibitory Activities J. Med. Chem. 2009, 52, 1873-1884 10.1021/jm801335z
137. 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 10.1021/jm100319h
138. Caporuscio, F.; Rastelli, G.; Imbriano, C.; Del Rio, A. Structure-Based Design of Potent Aromatase Inhibitors by High-Throughput Docking J. Med. Chem. 2011, 54, 4006-4017 10.1021/jm2000689
139. Neves, M. A.; Dinis, T. C.; Colombo, G.; Sa e Melo, M. L. An Efficient Steroid Pharmacophore-Based Strategy to Identify New Aromatase Inhibitors Eur. J. Med. Chem. 2009, 44, 4121-4127 10.1016/j.ejmech.2009.05.003
140. Nikolic, A. R.; Petri, E. T.; Klisuric, O. R.; Celic, A. S.; Jakimov, D. S.; Djurendic, E. A.; Penov Gasi, K. M.; Sakac, M. N. Synthesis and Anticancer Cell Potential of Steroidal 16,17-Seco-16,17a-Dinitriles: Identification of a Selective Inhibitor of Hormone-Independent Breast Cancer Cells Bioorg. Med. Chem. 2015, 23, 703-711 10.1016/j.bmc.2014.12.069
141. Vosooghi, M.; Firoozpour, L.; Rodaki, A.; Pordeli, M.; Safavi, M.; Ardestani, S. K.; Dadgar, A.; Asadipour, A.; Moshafi, M. H.; Foroumadi, A. Design, Synthesis, Docking Study and Cytotoxic Activity Evaluation of Some Novel Letrozole Analogs Daru, J. Pharm. Sci. 2014, 22, 83 10.1186/s40199-014-0083-4
142. Vasavi, H. S.; Arun, A. B.; Rekha, P. D. Anti-Quorum Sensing Activity of Flavonoid-Rich Fraction from Centella Asiatica L. Against Pseudomonas aeruginosa PAO1. J. Microbiol., Immunol. Infect. 2014, 10.1016/j.jmii.2014.03.012.
143. Mirzaie, S.; Chupani, L.; Asadabadi, E. B.; Shahverdi, A. R.; Jamalan, M. Novel Inhibitor Discovery against Aromatase through Virtual Screening and Molecular Dynamic Simulation: A Computational Approach in Drug Design Exp. Clin. Sci. J. 2013, 12, 168-183
144. Narayana, B. L.; Pran Kishore, D.; Balakumar, C.; Rao, K. V.; Kaur, R.; Rao, A. R.; Murthy, J. N.; Ravikumar, M. Molecular Modeling Evaluation of Non-Steroidal Aromatase Inhibitors† Chem. Biol. Drug Des. 2012, 79, 674-682 10.1111/j.1747-0285.2011.01277.x
145. Nagar, S.; Islam, M. A.; Das, S.; Mukherjee, A.; Saha, A. Pharmacophore Searching of Benzofuran Derivatives for Selective CYP19 Aromatase Inhibition Lett. Drug Des. Discovery 2009, 6, 38-45 10.2174/157018009787158607
146. Dai, Y.; Wang, Q.; Zhang, X.; Jia, S.; Zheng, H.; Feng, D.; Yu, P. Molecular Docking and Qsar Study on Steroidal Compounds as Aromatase Inhibitors Eur. J. Med. Chem. 2010, 45, 5612-5620 10.1016/j.ejmech.2010.09.011
147. Roy, P. P.; Roy, K. Molecular Docking and QSAR Studies of Aromatase Inhibitor Androstenedione Derivatives J. Pharm. Pharmacol. 2010, 62, 1717-1728 10.1111/j.2042-7158.2010.01154.x
148. Muftuoglu, Y.; Mustata, G. Pharmacophore Modeling Strategies for the Development of Novel Nonsteroidal Inhibitors of Human Aromatase (CYP19) Bioorg. Med. Chem. Lett. 2010, 20, 3050-3064 10.1016/j.bmcl.2010.03.113
149. Prakash, O.; Ahmad, A.; Tripathi, V. K.; Tandon, S.; Pant, A. B.; Khan, F. In Silico Assay Development for Screening of Tetracyclic Triterpenoids as Anticancer Agents against Human Breast Cancer Cell Line MCF7 PLoS One 2014, 9, e111049 10.1371/journal.pone.0111049
150. Petkov, P. I.; Temelkov, S.; Villeneuve, D. L.; Ankley, G. T.; Mekenyan, O. G. Mechanism-Based Categorization of Aromatase Inhibitors: A Potential Discovery and Screening Tool SAR QSAR Environ. Res. 2009, 20, 657-678 10.1080/10629360903438347
151. Hernandez-Guzman, F. G.; Higashiyama, T.; Pangborn, W.; Osawa, Y.; Ghosh, D. Structure of Human Estrone Sulfatase Suggests Functional Roles of Membrane Association J. Biol. Chem. 2003, 278, 22989-22997 10.1074/jbc.M211497200
152. Cojocaru, V.; Winn, P. J.; Wade, R. C. The Ins and Outs of Cytochrome P450s Biochim. Biophys. Acta, Gen. Subj. 2007, 1770, 390-401 10.1016/j.bbagen.2006.07.005
153. Park, J.; Czapla, L.; Amaro, R. E. Molecular Simulations of Aromatase Reveal New Insights into the Mechanism of Ligand Binding J. Chem. Inf. Model. 2013, 53, 2047-2056 10.1021/ci400225w
154. Sgrignani, J.; Magistrato, A. Influence of the Membrane Lipophilic Environment on the Structure and on the Substrate Access/Egress Routes of the Human Aromatase Enzyme. A Computational Study J. Chem. Inf. Model. 2012, 52, 1595-1606 10.1021/ci300151h
155. Catalano, S.; Barone, I.; Giordano, C.; Rizza, P.; Qi, H.; Gu, G.; Malivindi, R.; Bonofiglio, D.; Ando, S. Rapid Estradiol/ER alpha Signaling Enhances Aromatase Enzymatic Activity in Breast Cancer Cells Mol. Endocrinol. 2009, 23, 1634-1645 10.1210/me.2009-0039
156. Barone, I.; Giordano, C.; Malivindi, R.; Lanzino, M.; Rizza, P.; Casaburi, I.; Bonofiglio, D.; Catalano, S.; Ando, S. Estrogens and PTP1B Function in a Novel Pathway to Regulate Aromatase Enzymatic Activity in Breast Cancer Cells Endocrinology 2012, 153, 5157-5166 10.1210/en.2012-1561
157. Gillies, G. E.; McArthur, S. Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines Pharmacol. Rev. 2010, 62, 155-198 10.1124/pr.109.002071
158. Roselli, C. E.; Liu, M.; Hurn, P. D. Brain Aromatization: Classic Roles and New Perspectives Semin. Reprod. Med. 2009, 27, 207-217 10.1055/s-0029-1216274
159. Balthazart, J.; Ball, G. F. Is Brain Estradiol a Hormone or a Neurotransmitter? Trends Neurosci. 2006, 29, 241-249 10.1016/j.tins.2006.03.004
160. McEwen, B. S.; Alves, S. E. Estrogen Actions in the Central Nervous System Endocr. Rev. 1999, 20, 279-307 10.1210/edrv.20.3.0365
161. Sevrioukova, I. F.; Li, H.; Zhang, H.; Peterson, J. A.; Poulos, T. L. Structure of a Cytochrome P450-Redox Partner Electron-Transfer Complex Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 1863-1868 10.1073/pnas.96.5.1863
162. Aguilar, J. A.; Martin, H. L.; Mc, N. F. Aminoglutethimide in the Treatment of Epilepsy Can. Med. Assoc. J. 1961, 84, 374-376
163. Brodie, A. M.; Schwarzel, W. C.; Shaikh, A. A.; Brodie, H. J. The Effect of an Aromatase Inhibitor, 4-Hydroxy-4-Androstene-3,17-Dione, on Estrogen-Dependent Processes in Reproduction and Breast Cancer Endocrinology 1977, 100, 1684-1695 10.1210/endo-100-6-1684
164. Brodie, A. M.; Garrett, W. M.; Hendrickson, J. R.; Tsai-Morris, C. H.; Marcotte, P. A.; Robinson, C. H. Inactivation of Aromatase in Vitro by 4-Hydroxy-4-Androstene-3,17-Dione and 4-Acetoxy-4-Androstene-3,17-Dione and Sustained Effects in Vivo Steroids 1981, 38, 693-702 10.1016/0039-128X(81)90087-8
165. Steele, R. E.; Mellor, L. B.; Sawyer, W. K.; Wasvary, J. M.; Browne, L. J. In Vitro and in Vivo Studies Demonstrating Potent and Selective Estrogen Inhibition with the Nonsteroidal Aromatase Inhibitor Cgs 16949a Steroids 1987, 50, 147-161 10.1016/0039-128X(83)90068-5
166. Giudici, D.; Ornati, G.; Briatico, G.; Buzzetti, F.; Lombardi, P.; di Salle, E. 6-Methylenandrosta-1,4-Diene-3,17-Dione (FCE24304): A New Irreversible Aromatase Inhibitor J. Steroid Biochem. 1988, 30, 391-394 10.1016/0022-4731(88)90129-X
167. Zaccheo, T.; Giudici, D.; Lombardi, P.; di Salle, E. A New Irreversible Aromatase Inhibitor, 6-Methylenandrosta-1,4-Diene-3,17-Dione (FCE 24304): Antitumor Activity and Endocrine Effects in Rats with Dmba-Induced Mammary Tumors Cancer Chemother. Pharmacol. 1989, 23, 47-50 10.1007/BF00258457
168. Bhatnagar, A. S.; Hausler, A.; Schieweck, K.; Lang, M.; Bowman, R. Highly Selective Inhibition of Estrogen Biosynthesis by CGS 20267, a New Non-Steroidal Aromatase Inhibitor J. Steroid Biochem. Mol. Biol. 1990, 37, 1021-1027 10.1016/0960-0760(90)90460-3
169. Goss, P. E.; Powles, T. J.; Dowsett, M.; Hutchison, G.; Brodie, A. M.; Gazet, J. C.; Coombes, R. C. Treatment of Advanced Postmenopausal Breast Cancer with an Aromatase Inhibitor, 4-Hydroxyandrostenedione: Phase II Report Cancer Res. 1986, 46, 4823-4826
170. Demers, L. M.; Lipton, A.; Harvey, H. A.; Kambic, K. B.; Grossberg, H.; Brady, C.; Santen, R. J. The Efficacy of Cgs 20267 in Suppressing Estrogen Biosynthesis in Patients with Advanced Stage Breast Cancer J. Steroid Biochem. Mol. Biol. 1993, 44, 687-691 10.1016/0960-0760(93)90283-3
171. Iveson, T. J.; Smith, I. E.; Ahern, J.; Smithers, D. A.; Trunet, P. F.; Dowsett, M. Phase I Study of the Oral Nonsteroidal Aromatase Inhibitor CGS 20267 in Postmenopausal Patients with Advanced Breast Cancer J. Clin. Endocrinol. Metab. 1993, 53, 266-270 10.1210/jcem.77.2.8345035
172. Kitawaki, J.; Yamamoto, T.; Urabe, M.; Tamura, T.; Inoue, S.; Honjo, H.; Okada, H. Selective Aromatase Inhibition by Pyridoglutethimide, an Analogue of Aminoglutethimide Eur. J. Endocrinol. 1990, 122, 592-598 10.1530/acta.0.1220592
173. Bhatnagar, A. S. The Discovery and Mechanism of Action of Letrozole Breast Cancer Res. Treat. 2007, 105 (Suppl. 1) 7-17 10.1007/s10549-007-9696-3
174. Zhou, D. J.; Pompon, D.; Chen, S. A. Stable Expression of Human Aromatase Complementary DNA in Mammalian Cells: A Useful System for Aromatase Inhibitor Screening Cancer Res. 1990, 50, 6949-6954
175. Gibson, L.; Lawrence, D.; Dawson, C.; Bliss, J. Aromatase Inhibitors for Treatment of Advanced Breast Cancer in Postmenopausal Women Cochrane Database Syst. Rev. 2009, CD003370 10.1002/14651858.CD003370.pub3
176. Demers, L. M.; Boucher, A. E.; Santen, R. J. Aminoglutethimide Therapy in Breast Cancer: Relationship of Blood Levels to Drug-Related Side Effects Clin. Physiol. Biochem. 1987, 5, 287-291
177. Lawrence, B.; Santen, R. J.; Lipton, A.; Harvey, H. A.; Hamilton, R.; Mercurio, T. Pancytopenia Induced by Aminoglutethimide in the Treatment of Breast Cancer Cancer Treat. Rep. 1978, 62, 1581-1583
178. Rowell, N. P.; Gilmore, O. J.; Plowman, P. N. Aminoglutethimide as Second-Line Hormonal Therapy in Advanced Breast Cancer: Response and Toxicity Hum. Exp. Toxicol. 1987, 6, 227-232 10.1177/096032718700600310
179. 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 10.1210/jcem-69-4-896
180. Falkson, G.; Raats, J. I.; Falkson, H. C. Fadrozole Hydrochloride, a New Nontoxic Aromatase Inhibitor for the Treatment of Patients with Metastatic Breast Cancer J. Steroid Biochem. Mol. Biol. 1992, 43, 161-165 10.1016/0960-0760(92)90202-T
181. Lonning, P. E.; Geisler, J. Experience with Exemestane in the Treatment of Early and Advanced Breast Cancer Expert Opin. Drug Metab. Toxicol. 2008, 4, 987-997 10.1517/17425255.4.7.987
182. Tominaga, T.; Adachi, I.; Sasaki, Y.; Tabei, T.; Ikeda, T.; Takatsuka, Y.; Toi, M.; Suwa, T.; Ohashi, Y. Double-Blind Randomised Trial Comparing the Non-Steroidal Aromatase Inhibitors Letrozole and Fadrozole in Postmenopausal Women with Advanced Breast Cancer Ann. Oncol. 2003, 14, 62-70 10.1093/annonc/mdg014