Letters
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 22 6775
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References
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Figure 2. (A) Superimposed crystal structures of 16 (yellow)
and 17 (teal) bound to the ligand binding domain of ERR. (B)
Orientation of 16 in ERR.
investigate this possibility, we independently crystal-
lized 16 and 17 in the ligand binding domain of ERR.
As shown in the overlay for these two crystal structures
(Figure 2A), the overall protein-ligand architectures of
the ligand-bound monomers are very similar, including
the position of helix 12, indicating that at the crystal-
lographic level 16 does not induce a conformation that
is substantially different from that of 17. One particular
note of interest (Figure 2B) is that the methyl sulfone
in 16 interacts with the His 524 side chain via a H-bond
(3.3 Å) and thus represents a novel phenol mimic among
ER ligands.
In summary, we have identified a novel ovarian
selective SERM (16) that demonstrates a wide thera-
peutic window between the desired antagonistic effects
on the uterus and the undesirable side effects on the
ovaries. In addition, bone studies demonstrate that 16
prevents ovariectomy-induced bone loss in OVX rats and
does not cause bone loss in ovary-intact rats, data which
support estrogen agonist effects on skeletal tissue.17 As
such, this compound has therapeutic potential for the
treatment of leiomyomas in premenopausal women and
is currently in clinical development.
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for estrogen action. Proc. Natl. Acad. Sci. U.S.A. 1977, 74, 3162-
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(17) Geiser, A. G.; Hummel, C. W.; Draper, M. W.; Henck, J. W.
Cohen, I. R.; Rudmann, D. G.; Donnelly, K. B.; Adrian, M. D.;
Shepherd, T. A.; Wallace, O. B.; McCann, D. J.; Oldham, S. W.;
Bryant, H. U.; Sato, M.; Dodge, J. A. A new selective estrogen
receptor modulator (SERM) with potent uterine antagonist
activity, agonist activity in bone, and minimal ovarian
stimulation Endocrinology 2005, 10.1210/en2005-0024. See
Publication format.
Acknowledgment. We thank Lead Optimization
Biology, M. Dee Adrian, Harlan Cole, Cassandra Gauth-
ier, Norman Hughes, Sam Oldham, Ellen Rowley, Pam
Shetler, and Tim Richardson.
Supporting Information Available: Experimental pro-
cedures for 9, 16, and 17, elemental analysis results, protocols
for all in vitro and in vivo assays, and crystallographic
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