Q. Tan et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3753–3755
Table 1. Human ER bindinga and inhibition of MCF-7 cell growth
3755
2. Representative SERMs: EVISTA: Grese, T. A.; Penning-
ton, L. D.; Sluka, J. P.; Adrian, M. D.; Cole, H. W.; Fuson,
T. R.; Magee, D. E.; Phillips, D. L.; Rowley, E. R.; Shetler,
P. K.; Short, L. L.; Venugopalan, M.; Yang, N. N.; Sato,
M.; Glasebrook, A. L.; Bryant, H. U. J. Med. Chem. 1998,
41, 1272; NALVADEX: Jordan, V. C. Br. J. Pharmacol.
1993, 110, 507; EM-652, SCH57068: Labrie, M.; Labrie, C.;
Belanger, A.; Simard, J.; Giguere, V.; Tremblay, A.;
Tremblay, G. J. Steroid. Biochem. Mol. Biol. 2001, 79,
213; Lasofoxifene: Ke, H. Z.; Paralkar, V. M.; Grasser, W.
A.; Crawford, D. T.; Qi, H.; Simmons, H. A.; Pirie, C. M.;
Chidsey-Frink, K. L.; Owen, T. A.; Smock, S. L.; Chen, H.
K.; Jee, W. S. S.; Cameron, K. O.; Rosati, R. L.; Brown, T.
A.; DaSilva Jardine, P.; Thompson, D. D. Endocrinology
1998, 139, 2068; Bazedoxifene: Miller, C. P.; Collini, M. D.;
Tran, B. D.; Harris, H. A.; Kharode, Y. P.; Marzolf, J. T.;
Moran, R. A.; Henderson, R. A.; Bender, R. H. W.;
Unwalla, R. J.; Greenberger, L. M.; Yardley, J. P.; Abou-
Gharbia, M. A. A.; Lyttle, C. R.; Komm, B. S. J. Med.
Chem. 2001, 44, 1654.
Compoundb
Binding affinity, IC50 (nM)
ERa/ERb (fold selective for
ERa)
MCF-7 inhibition
IC50 (nM)
1
4/161 (40)
15/583 (39)
4/87 (22)
152
564
114
67
2
3
4
5/111 (22)
18/266 (15)
21/326 (16)
0.8/45 (56)d
1.0/38 (38)f
4/115 (29)h
1.3/1.1 (1)j
5
123
112
3.0e
0.6g
0.4i
––
6
Ic
IIc
IIIc
Estradiol
a The single IC50 values were generated in an estrogen receptor ligand
binding assay. This scintillation proximity assay was conducted in
NEN basic flashplates using tritiated estradiol and full length re-
combinant human ERa and ERb proteins, with an incubation time of
3 h. In our experience, this assay provides IC50 values that are
reproducible to within a factor of 2–3.
3. (a) Kuiper, G. G. J. M.; Enmark, E.; Pelto-Huikko, M.;
Nilsson, S.; Gustafsson, J. A. Proc. Natl. Acad. Sci. U.S.A.
1996, 93, 5925; (b) Mosselman, S.; Polman, J.; Dijkema, R.
FEBS Lett. 1996, 392, 49.
b All new dihydrobenzodithiins are racemic and were characterized
spectroscopically.
c Chiral.
d Average of 36 measurements.
4. (a) Kim, S.; Wu, J. Y.; Birzin, E. T.; Frisch, K.; Chan, W.;
Pai, L.-Y.; Yang, Y. T.; Mosley, R. T.; Fitzgerald, P. M.
D.; Sharma, N.; Dahllund, J.; Thorsell, A.-G.; DiNinno,
F.; Rohrer, S. P.; Schaeffer, J. M.; Hammond, M. L.
J. Med. Chem. 2004, 47, 2171; (b) Chen, H. Y.; Kim, S.;
Wu, J. Y.; Birzin, E. T.; Chan, W.; Yang, Y. T.; DiNinno,
F.; Rohrer, S. P.; Schaeffer, J. M.; Hammond, M. L.
Bioorg. Med. Chem. Lett. 2004, 14, 2551; (c) Kim, S.; Wu, J.
Y.; Chen, H. Y.; Birzin, E. T.; Chan, W.; Pai, L.-Y.; Yang,
Y. T.; Colwell, L.; Li, S.; Dahllund, J.; DiNinno, F.;
Rohrer, S. P.; Schaeffer, J. M.; Hammond, M. L. Bioorg.
Med. Chem. Lett. 2004, 14, 2741; (d) Tan, Q.; Birzin, E. T.;
Chan, W.; Yang, Y. T.; Pai, L.-Y.; Hayes, E. C.; DaSilva,
C. A.; DiNinno, F.; Rohrer, S. P.; Schaeffer, J. M.;
Hammond, M. L. Bioorg. Med. Chem. Lett. 2004, 14,
in press; (e) DiNinno, F. P.; Chen, H. Y.; Kim, S.; Wu,
J. Y. International Patent WO200232377.
e Average of 7 measurements.
f Average of 101 measurements.
g Average of 5 measurements.
h Average of 2 measurements.
i Average of 2 measurements.
j Average of 130 measurements.
changes and has prompted future work toward under-
standing the SAR of the dihydrobenzoxathiin SERAM
platform.
References and notes
1. Recent reviews on SERMs: (a) Jordan, V. C. J. Med. Chem.
2003, 46, 883; (b) Jordan, V. C. J. Med. Chem. 2003, 46,
1081; (c) Meegan, M. J.; Lloyd, D. G. Curr. Med. Chem.
2003, 10, 181; (d) Miller, C. P. Curr. Pharm. Des. 2002, 8,
2089; (e) Bryant, H. U. Endocr. Metabol. Disord. 2002, 3,
231.
5. Kim, S.; Wu, J. Y.; Chen, H. Y.; DiNinno, F. Org. Lett.
2003, 5, 685.
6. Bromoketone 16 was obtained via a-bromination (THF,
PTAB, 0 °C to rt, 79%) of the corresponding ketone, which
was made according to the method in Ref. 4a,b.