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amine mutagenic potential, this change resulted in an
order of magnitude loss in binding affinity, and so as a
general rule (also considering the inverse correlation of
mutagenic potential with the number of fused rings),
we chose to limit our SAR explorations to monocyclic
aryl substitutions into this scaffold. Both dramatic steric
and electronic effects were seen in response to substitu-
ent changes in these two positions. Substitution ortho
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1
atropoisomerism, readily observable by H NMR. This
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conformational restriction and presumed consequent
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of Cl-analogue 11), as compounds 8–12 suffer at least a
30-fold loss in potency, despite maintaining reasonable
binding affinity. Size limitations appeared to exist at
R2, as seen with compound 12. In the absence of coun-
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by the addition of a simple methyl group at R1 (compare
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¨
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Electron donating groups appear to be poorly tolerated
throughout (as in 9, 17, 18, 26, 28, and 29), perhaps due
to attenuation of the strength of aryl p-edge/face interac-
tions with F764 in the AR LBD, as well as reduced
H-bonding capacity of the CN group. The presence of
two lipophilic and/or electron-withdrawing groups ap-
peared optimal at both R1 and R2, with halogen and
methyl groups generally optimal. All SARMs discov-
ered in this series with EC50’s < 5 nM follow this trend
(i.e., 11, 14, 16, 19–22, 24, and 27). The most potent
agonists (EC50 < 1 nM) were those where R1 = Me and
R2 = halogen (20 and 21).
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With respect to mutagenic potential, less clear SAR
trends emerged. Naphthylamine 2 was definitively muta-
genic in both SOS Chromotest and Ames assays. Con-
sistent with known aniline mutagenicity SAR, the aryl
amine components of several compounds without steric
encumbrance proximal to the amino group showed a
positive mutagenic response in one or both assays
(e.g., those from 9 and 11). Likely owing to the success
of aniline pre-selection criteria, most of the anilines test-
ed in the overall series were negative in the SOS Chro-
motest, and the generally high predictive power of this
assay was consistent within this group of anilines (with
the exception of that from 9). Though only a subset of
anilines were tested in Ames assays, no false positives
were observed in the SOS Chromotest, a desirable
feature in optimizing this parameter in concert with
pharmacological endpoints. Consequently, increasing
the throughput and decreasing the compound require-
ment for a mutagenicity screen allowed for the iterative
optimization of both efficacy and mutagenicity in paral-
lel, resulting in the rapid elimination of this unaccept-
able liability and identification of compound 20, which
advanced to human clinical trials.20,21
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References and notes
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