P. Marchand et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1553–1555
1555
Considering the aromatase inhibitors carrying the imi-
dazolyl substituent, it is evident that the oxidation of
the indoline to indole had no pharmacological effect
and both compounds 5a, 12a and 5b, 12b exhibited the
same range of activity (Table 1). The most active com-
pound was the 1-ethyl-7-[(imidazol-1-yl)(4-chlorophenyl)
methyl]-1H-indole 12c with IC50: 0.055 mM and rp: 336
but all compounds bearing halogen atom in the 4-posi-
tion of phenyl nucleus also remained potent aromatase
inhibitors, except 13a. Moreover, the nature of the
halogen did not appear to be an essential requirement
for inhibitory activity as showed the close and high rp
values of 12a (R1=4-F, rp: 298.4), 12c (R1=4-Cl, rp:
336) and 12d (R1=Br, rp: 264).
activity of our imidazoles by testing enantiomerically
pure compounds as vorozole, for instance.
The triazole analogue 7a was prepared with the aim of
exploring the effects of the variation of the aza-hetero-
cycle. It has been reported that the replacement of the
imidazole moiety with a triazole one can lead to higher
in vivo activity.18
Further experiments on the in vivo inhibitory activity
and on the selectivity towards other steroidogenic P450
enzymes such as P450 scc will be performed.
References and Notes
On the one hand, in the indole series, the introduction
of a bromine into the 5-position led to markedly
decrease the P450 arom inhibition (compound 13a, rp:
92.5). On the other hand, in the indoline series, the
replacement of an hydrogen by a bromine (6a, rp: 205.6)
had a negative effect on inhibitory aromatase activity
and the presence of a chlorine (60a, rp: 293.6) influenced
only moderately this activity by comparison with 5a
showing a relative potency of 300.8.
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For the triazole compound 7a, the aromatase assay was
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itoring enzyme activity by measuring 3H2O formed from
[1b-3H]androstenedione during aromatization. The
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7. Marchand, P.; Le Borgne, M.; Duflos, M.; Robert-Pies-
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J. Med. Chem. 1984, 27, 1379.
a triazolyl substituent (compound 7a) strongly
decreased the inhibition of P450 arom.
Percent inhibition values of P450 17a indicate that all
compounds do not significantly inhibit the enzyme or
show only marginal inhibitory activity at 2.5 mM.
12. Jones, C. D.; Winter, M. A.; Hirsch, K. S.; Stamm, N.;
Taylor, H. M.; Holden, H. E.; Davenport, J. D.; Krumkalns,
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Conclusion
We have discovered new 7-(a-azolylbenzyl)-1H-indoles
and indolines as potent and selective aromatase inhibi-
tors but less active than an analogue in the 5-position
previously synthesized and tested by us9 (compound I,
rp: 451.2).
The next step of the work will be the separation of the
most active racemic compounds 5a, 60a, 12a and 12c, by
chiral HPLC, so as to enhance the P450 arom inhibitory
17. Graves, P. E.; Salhanick, H. A. Endocrinology 1979, 105, 52.
18. Lang, M.; Batzl, C.; Furet, P.; Bowman, R.; Hausher, A.;
¨
Bhatnagar, A. S. J. Steroid Biochem. Mol. Biol. 1993, 44, 421.