1
26
J. C. Lanter et al. / Bioorg. Med. Chem. Lett. 17 (2007) 123–126
15, 1565; (b) Chen, J.; Kim, J.; Dalton, J. T. Mol.
Interventions 2005, 5, 173.
1
1
1
20
10
00
5
. (a) Lanter, J. C.; Sui, Z.; Fiordeliso, J. J.; Jiang, W.;
Zhang, X. U.S. Pat. Appl. Publ. 200525074, 2005; (b)
Lanter, J. C.; Sui, Z.; Fiordeliso, J. J.; Jiang, W.; Zhang,
X. U.S. Pat. Appl. Publ. 2005250740, 2005; (c) Lanter, J.
C.; Sui, Z.; Fiordeliso, J. J.; Jiang, W.; Zhang, X. U.S. Pat.
Appl. Publ. 2005245485, 2005; (d) Lanter, J. C.; Sui, Z.;
Fiordeliso, J. J. U.S. Patent 6,858,621, 2005.
9
8
7
0
0
0
%
Pros.
Wt.
Inh 60
5
4
3
2
1
0
0
0
0
0
0
6. (a) Lima, L. M.; Barreiro, E. J. Curr. Med. Chem. 2005,
12, 23; (b) Kier, L. B.; Hall, L. H. Chem. Biodivers. 2004,
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J. Chem. Rev. 1996, 96, 3147.
-
-
-
10
20
30
7
. A typical procedure: A modified Hershberger assay
(
Hershberger, L. G.; Shipley, E. G.; Meyer, R. K.;
Myotrophic activity of 19-nortestosterone and other
steroids determined by modified levator ani muscle
method. Proc. Soc. Exp. Biol. Med. 1953 83, 175) was
performed to assess androgen antagonist activity in
orchidectomized rats. Sprague–Dawley rats (Charles Riv-
er Laboratories, Wilmington, MA) were castrated at three
weeks old. They were then dosed once daily for five days
with test compound (oral dosing by gavage needle; vehicle:
0.03
0.1
0.3
1
3
Dose Compound (mg/d)
(
(
+)-6i
-) -6i
4
(Casodex ®)
3
0% (w/v) hydroxypropyl-b-D-cyclodextrin [Cargil Inc.,
Cedar Rapids, IA]) in the presence of 0.1 mg/day (approx-
imately 1.3 mg/kg) testosterone propionate (subcutaneous
dosing; vehicle: sesame oil). At necropsy, ventral prostates
and seminal vesicles were removed and their wet weights
were measured. Tissue weights were divided by whole
body weight. Data were expressed as percentage of
inhibition relative to testosterone alone (0% inhibition)
and cyclodextrin vehicle alone (100% inhibition).
Figure 3. Dose–response curves of prostate weight reduction for
bicalutamide, (+)-6i, and (À)-6i in immature rats.
tigation of the indole carbinol nucleus for the purpose of
uncovering novel antiandrogens. This approach also
highlights the utility of the Hershberger assay as a
means of rapidly developing in vivo androgen receptor
SAR.
8
9
. Gladiali, S.; Pinna, L. Tetrahedron: Asymmetry 1991, 2,
6
23.
. Boger, D. L.; McKie, J. A. J. Org. Chem. 1995, 60,
271.
1
1
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J. K., Ed.; IRL Press: Oxford, UK, 1994; pp 217–235; (b)
Sakamoto, Takao; Kondo, Yoshinori; Iwashita, Shigeki;
Nagano, Tatsuo; Yamanaka, Hiroshi. Pharm. Inst.,
Tohoku Univ., Sendai, Japan. Chem. Pharm. Bull. 1988,
Acknowledgment
The authors thank Professor Dale Boger for his sugges-
tions regarding the iodination of electron deficient
anilines.
3
6, 1305.
1. Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem.
998, 63, 7652.
1
1
1
2. Ho, B.-T.; Li, K.-C.; Walker, K. E.; Tansey, L. W.;
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