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2327
in DMF at 0 °C followed by the addition of the benzyl
bromide 16 to provide 17 in 90% yield.
References and notes
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The reduction of the ketone 17 with (R)-2-methyl-CBZ-
oxazoboroline in THF at 0 °C afforded the desired chiral
alcohol 18 (81% ee).13 Conversion of 18 to the azide
using DPPA and DBU afforded separable mixtures of
the desired azide 19 and the vinyl product 20. Similar at-
tempts to prepare 19 from activating the alcohol 18 via
the mesylate or using Mitsunobu conditions afforded
only the elimination by-product 20.
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The displacement reaction of 19 using piperidine or with
b-methyl pyrrolidine,7j followed by reduction of the
azide, yielded the pivotal amines 21a–b. In turn, 21a–b
were coupled using EDC in 1:1 DCM/DMSO with cat-
alytic DMAP and 3-indole acetic acid (2), followed by
subsequent deprotection of the TIPS protecting group
using TBAF and chiral resolution of the enantiomerical-
ly enriched products using chiral HPLC14 to afford the
desired bazedoxifene-like derivatives 22a–b.
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The biological evaluation of 22b (Table 3) demonstrated
high affinity and selectivity for ERa (ꢀ130-fold) while
showing moderately improved antagonism (76%). Inter-
estingly, 22a bearing a chiral b-methyl pyrroline side
chain, found to impart exceptional antagonism in the di-
hydrobenzoxathiin series,7i provided only a modest gain
in antagonism. This observation was similarly reported
by Blizzard et al.7k regarding the SAR of SERMs pos-
sessing the super antagonist side chains.
7. (a) Chen, H. Y.; Dykstra, K. D.; Birzin, E. T.; Frisch, K.;
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Although excellent potency and selectivity for this class
was maintained, measures of MCF-7 cell proliferation
for both 22a and 22b were less than those observed with
our prior classes of compounds.
In conclusion, we have discovered a novel class of 2-aryl
indoles that have high subtype selectivity and high affin-
ity for ERa, while demonstrating in vivo antagonism.
The interactions of the basic side chain, in the case of
11f, with the Asp 351 residue in ERa confirmed our
molecular modeling hypothesis.
In addition, the combination of bazedoxifene or similar
SERM platforms that adopt the required antagonist
confirmation, with the subtype selective acetamide link-
er, could lead to novel SERAMs with unique biological
profiles and tissue selectivities.
Acknowledgments
The senior author greatfully acknowledges the guidance
and mentorship of Dr. Frank DiNinno, whose dedica-
tion to this and other efforts over his illustrious career
at Merck will always be fondly remembered. The
authors thank Dr. Mats Carlquist and his colleagues
at Karo-Bio for providing protein samples and diffrac-
tion data. Use of the Advanced Photon Source beamline
17-ID was supported by the companies of the Industrial
Macromolecular Crystallography Association through a
contract with Illinois Institute of Technology.