Synthesis and structure–activity relationships of analogs of EM-652 (acolbifene), a pure selective estrogen receptor modulator. Study of nitrogen substitution

References

• Grese TA, Dodge JA. Selective estrogen receptor modulators (SERMs). Curr Pharm Des 1998;4:71–92.
   PubMed Web of Science ®Google Scholar
• Henderson BE, Ross R, Bernstein L. Estrogens as a cause of human cancer: The Richard and Hinda Rosenthal Foundation award lecture. Cancer Res 1988;48:246–253.
   PubMed Web of Science ®Google Scholar
• Ciocca DR, Roig LMV. Estrogen receptors in human nontarget tissues: Biological and clinical implications. Endocr Rev 1995;16:35–62.
   PubMed Web of Science ®Google Scholar
• Ciocca RG, Choi J, Graham AM. Antiphospholipid antibodies lead to increased risk in cardiovascular surgery. Am J Surg 1995;170:198–200.
   PubMed Web of Science ®Google Scholar
• Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 1994;331:1056–1061.
   PubMed Web of Science ®Google Scholar
• McGuire WL, Carbone PP, Seard ME, Esche GC In: McGuire WL, Carbone PP, Vollmer EP, editors. Estrogen Receptors in Human Breast Cancer. New York: Raven Press; 1975. p 1–7.
   Google Scholar
• Davidson NE, Lippman ME. The role of estrogens in growth regulation of breast cancer. Crit Rev Oncog 1989;1:89–111.
   PubMedGoogle Scholar
• Mouridsen H, Palshof T, Patterson J, Battersby L. Tamoxifen in advanced breast cancer. Cancer Treat Rev 1978;5:131–141.
   PubMed Web of Science ®Google Scholar
• Dickson RB, Lippman ME. Estrogenic regulation of growth and polypeptide growth factor secretion in human breast carcinoma. Endocr Rev 1987;8:29–43.
   PubMed Web of Science ®Google Scholar
• Horwitz KB, McGuire WL. Nuclear mechanisms of estrogen action. Effects of estradiol and anti-estrogens on estrogen receptors and nuclear receptor processing. J Biol Chem 1978;253:8185–8191.
   Google Scholar
• Wakeling AE. The future of new pure antiestrogens in clinical breast cancer. Breast Cancer Res Treat 1993;25:1–9.
   PubMed Web of Science ®Google Scholar
• Furr BJ, Jordan VC. The pharmacology and clinical uses of tamoxifen. Pharmac Ther 1984;25:127–205.
   PubMed Web of Science ®Google Scholar
• MacNab MW, Tallarida RJ, Joseph R. An evaluation of tamoxifen as a partial agonist by classical receptor theory — an explanation of the dual action of tamoxifen. Eur J Pharmacol 1984;103:321–326.
   PubMed Web of Science ®Google Scholar
• Poulin R, Me´rand Y, Poirier D, Le´vesque C, Dufour J-M, Labrie F. Antiestrogenic properties of keoxifene, trans-4- hydroxytamoxifen, and ICI 164384, a new steroidal antiestro- gen, in ZR-75-1 human breast cancer cells. Breast Cancer Res Treat 1989;14:65–76.
   PubMed Web of Science ®Google Scholar
• Labrie C, Martel C, Dufour J-M, Le´vesque C, Me´rand Y, Labrie F. Novel compounds inhibit estrogen formation and action. Cancer Res 1992;52:610–615.
   PubMed Web of Science ®Google Scholar
• Labrie F, Labrie C, Be´langer A, Gigue`re V, Simard J, Me´rand Y, Gauthier S, Luu-The V, Candas B, Martel C, Luo S. Pure selective estrogen receptor modulators, new molecules having absolute cell specificity ranging from pure antiestrogenic to complete estrogen-like activities. Adv Protein Chem 2001;56:293–368.
   PubMedGoogle Scholar
• Gauthier S, Caron B, Cloutier J, Dory YL, Favre A, Larouche D, Mailhot J, Ouellet C, Schwerdtfeger A, Leblanc G, Martel C, Simard J, Me´rand Y, Be´langer A, Labrie C, Labrie F. (S)- (þ)-4-[7-(2,2-Dimethyl-1-oxopropoxy)-4-methyl-2-[4-[2-(1- piperidinyl)-ethoxy]phenyl]-2H-1-benzopyran-3-yl]phenyl 2,2-Dimethylpropanoate (EM-800): A Highly Potent, Specific, and Orally Active Nonsteroidal Antiestrogen. J Med Chem 1997;40:2117–2122.
   PubMed Web of Science ®Google Scholar
• Labrie F, Labrie C, Be´langer A, Simard J, Gauthier S, Luu- The V, Me´rand Y, Gigue`re V, Candas B, Luo S, Martel C, Singh SM, Fournier M, Coquet A, Richard V, Charbonneau R, Charpenet G, Tremblay A, Tremblay G, Cusan L, Veilleux R. EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and endometrium. J Steroid Biochem Mol Biol 1999;69:51–84.
   PubMed Web of Science ®Google Scholar
• Labrie F, Labrie C, Be´langer A, Simard J, Gigue`re V, Tremblay A, Tremblay G. EM-652 (SCH57068), a pure SERM having complete antiestrogenic activity in the mammary gland and endometrium. J Steroid Biochem Mol Biol 2002;79:213–225.
   Web of Science ®Google Scholar
• Martel C, Provencher L, Li X, St. Pierre A, Leblanc G, Gauthier S, Me´rand Y, Labrie F. Binding characteristics of novel nonsteroidal antiestrogens to the rat uterine estrogen receptors. J Steroid Biochem Mol Biol 1998; 64:199–205.
   PubMed Web of Science ®Google Scholar
• Tremblay GB, Tremblay A, Copeland NG, Gilbert DJ, Jenkins NA, Labrie F, Gigue`re V. Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor b. Mol Endocrinol 1997;11:353–365.
   PubMed Web of Science ®Google Scholar
• Simard J, Labrie C, Be´langer A, Gauthier S, Singh SM, Me´rand Y, Labrie F. Characterization of the effects of the novel non-steroidal antiestrogen EM-800 on basal and estrogen-induced proliferation of T-47D, ZR-75-1 and MCF-7 human breast cancer cells in vitro. Int J Cancer 1997;73:104–112.
   PubMed Web of Science ®Google Scholar
• Martel C, Labrie C, Be´langer A, Gauthier S, Me´rand Y, Li X, Provencher L, Candas B, Labrie F. Comparison of the effects of the new orally active antiestrogen EM-800 with ICI 182 780 and toremifene on estrogen-sensitive parameters in the ovariectomized mouse. Endocrinol 1998;139:2486–2492.
   PubMed Web of Science ®Google Scholar
• Luo S, Sourla A, Labrie C, Be´langer A, Labrie F. Combined effects of dehydroepiandrosterone and EM-800 on bone mass, serum lipids, and the development of dimethylbenz(A)an- thracene-induced mammary carcinoma in the rat. Endocrinol 1997;138:4435–4444.
   PubMed Web of Science ®Google Scholar
• Luo S, Stojanovic M, Labrie C, Labrie F. Inhibitory effect of the novel anti-estrogen EM-800 and medroxyprogesterone acetate on estrone-stimulated growth of dimethylbenz[a] anthracene-induced mammary carcinoma in rats. Int J Cancer 1997;73:580–586.
   PubMed Web of Science ®Google Scholar
• Luo S, Labrie C, Be´langer A, Candas B, Labrie F. Prevention of development of dimethylbenz(a)anthracene (DMBA)- induced mammary tumors in the rat by the new nonsteroidal antiestrogen EM-800 (SCH57050). Breast Cancer Res Treat 1998;49:1–11.
   PubMed Web of Science ®Google Scholar
• Couillard S, Gutman M, Labrie C, Be´langer A, Candas B, Labrie F. Comparison of the effects of the antiestrogens EM- 800 and tamoxifen on the growth of human breast ZR-75-1 cancer xenografts in nude mice. Cancer Res 1998;58:60–64.
   PubMed Web of Science ®Google Scholar
• Couillard S, Labrie C, Be´langer A, Candas B, Pouliot F, Labrie F. Effect of dehydroepiandrosterone and the antiestro- gen EM-800 on growth of human ZR-75-1 breast cancer xenografts. J Natl Cancer Inst 1998;90:772–778.
   PubMedGoogle Scholar
• Couillard S, Gutman M, Labrie F, Candas B, Labrie C. Effect of combined treatment with the pure antiestrogen EM-800 and radiotherapy on the growth of human ZR-75-1 breast cancer xenografts in nude mice. Cancer Res 1999;59:4857–4863.
   PubMed Web of Science ®Google Scholar
• Gutman M, Couillard S, Labrie F, Candas B, Labrie C. Effects of the antiestrogen EM-800 (SCH 57050) and cyclophosphamide alone and in combination on growth of human ZR-75-1 breast cancer xenografts in nude mice. Cancer Res 1999;59:5176–5180.
   PubMed Web of Science ®Google Scholar
• Couillard S, Labrie C, Gauthier S, Me´rand Y, Singh SM, Candas B, Labrie F. Long-term inhibitory effect of the orally active and pure antiestrogen EM-800 on the growth of human breast cancer xenografts in nude mice. Int J Cancer 2000;85:424–429.
   PubMed Web of Science ®Google Scholar
• Gutman M, Couillard S, Roy J, Labrie F, Candas B, Labrie C. Comparison of the effects of EM-652 (SCH57068), tamox- ifen, toremifene, droloxifene, idoxifene, GW-5638 and raloxifene on the growth of human ZR-75-1 breast tumors in nude mice. Int J Cancer 2002;99:273–278.
   PubMed Web of Science ®Google Scholar
• Roy J, Couillard S, Gutman M, Labrie F. A novel pure SERM achieves complete regression of the majority of human breast cancer tumors in nude mice. Breast Cancer Res Treat 2003;81:223–229.
   PubMed Web of Science ®Google Scholar
• Martel C, Sourla A, Pelletier G, Labrie C, Fournier M, Picard S, Li S, Stojanovic M, Labrie F. Predominant androgenic component in the stimulatory effect of dehydroepiandroster- one on bone mineral density in the rat. J Endocrinol 1998;157:433–442.
   PubMed Web of Science ®Google Scholar
• Martel C, Picard S, Richard V, Be´langer A, Labrie C, Labrie F. Prevention of bone loss by EM-800 and raloxifene in the ovariectomized rat. J Steroid Biochem Mol Biol 2000;74:45–56.
   PubMed Web of Science ®Google Scholar
• Picard F, Deshaies Y, Lalonde J, Samson P, Labrie C, Be´langer A, Labrie F, Richard D. Effects of the estrogen antagonist EM- 652-HCl on energy balance and lipid metabolism in ovariectomized rats. Int J Obes 2000;24:830–840.
   PubMed Web of Science ®Google Scholar
• Brzozowski AM, Pike ACW, Dauter Z, Hubbard RE, Bonn T, Engstro¨m O, O¨ hman L, Greene GL, Gustafsson J-A°, Carlquist M. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997;389:753–758.
   Google Scholar
• Gauthier S, Cloutier J, Dory YL, Favre A, Mailhot J, Ouellet C, Schwerdtfeger A, Me´rand Y, Martel C, Simard J, Labrie F. Synthesis and structure-activity relationships of analogs of EM-652, a pure selective estrogen receptor modulator. Part 1: study of nitrogen substitution Abstracts of Papers. Washing- ton, DC: American Chemical Society; 2002., 223th National Meeting of the American Chemical Society, Orlando, FL, April 7-11, 2002MEDI-224.
   Google Scholar
• Al-Maharik NI, Kaltia SAA, Mutikainen I, Wa¨ha¨la¨ K. Synthesis of C-C-Bridged Bis-Isoflavones. J Org Chem 2000;65:2305–2308.
   PubMed Web of Science ®Google Scholar
• Sharma AP, Saeed A, Durani S, Kapil RS. Structure-activity relationship of antiestrogens. Phenolic analogs of 2,3-diaryl- 2H-1-benzopyrans. J Med Chem 1990;33:3222–3229.
   Google Scholar
• Asselin J, Kelly PA, Caron MG, Labrie F. Control of hormone receptor levels and growth of 7,12-dimethylbenz(a)anthra- cene-induced mammary tumors by estrogens, progesterone and prolactin. Endocrinol 1977;101:666–671.
   PubMed Web of Science ®Google Scholar
• Asselin J, Labrie F. Effects of estradiol and prolactin on steroid receptor levels in 7,12-dimethylbenz(a)anthracene-induced mammary tumors and uterus in the rat. J Steroid Biochem 1978;9:1079–1082.
   PubMedGoogle Scholar
• Rodbard D. Apparent positive cooperative effects in cyclic AMP and corticosterone production by isolated adrenal cells in response to ACTH analogs. Endocrinol 1974;94:1427–1437.
   PubMed Web of Science ®Google Scholar
• Simard J, Dauvois S, Haagensen DE, Le´vesque C, Me´rand Y, Labrie F. Regulation of progesterone-binding breast cyst protein GCDFP-24 secretion by estrogens and androgens in human breast cancer cells: a new marker of steroid action in breast cancer. Endocrinol 1990; 126:3223–3231.
   PubMed Web of Science ®Google Scholar
• Wa¨ha¨la¨ K, Hase TA. Expedient synthesis of polyhydroxy- isoflavones. J Chem Soc, Perkin Trans 1 1991;12:3005–3008.
   Google Scholar
• Draper RW, Hu B, Iyer RV, Li X, Lu Y, Rahman M, Vater EJ. An efficient process for the synthesis of trans-2,3-disubstituted 2,3-dihydro-4H-1-benzopyran-4-ones (chroman-4-ones). Tetrahedron 2000;56:1811–1817.
   Web of Science ®Google Scholar
• Hartman WW. b-DIETHYLAMINOETHYL ALCOHOL (Ethanol, 2-diethylamino-). In: Blatt AH, editor. Organic Syntheses. New York: John Wiley & Sons; 1943. p 183-184, collective volume 2.
   Google Scholar
• Grese TA, Sluka JP, Bryant HU, Cullinan GJ, Glasebrook AL, Jones CD, Matsumoto K, Palkowitz AD, Sato M, Termine JD, Winter MA, Yang NN, Dodge JA. Molecular determinants of tissue selectivity in estrogen receptor modulators. Proc Natl Acad Sci USA 1997;94:14105–14110.
   PubMed Web of Science ®Google Scholar
• Simard J, Sanchez R, Poirier D, Gauthier S, Singh SM, Me´rand Y, Be´langer A, Labrie C, Labrie F. Blockade of the stimulatory effect of estrogens, OH-tamoxifen, OH-toremi- fene, droloxifene, and raloxifene on alkaline phosphatase activity by the antiestrogen EM-800 in human endometrial adenocarcinoma Ishikawa cells. Cancer Res 1997;57:3494–3497.
   PubMed Web of Science ®Google Scholar