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C. Stiff et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6293–6297
OH
N
Br
N
O
N
S
O
47
O
Figure 3. X-ray structure of indazol 47.
Figure 5. Structural overlay of 47 (white) and Anthranilic acid 48
(green).
OH
N
ols are readily prepared via the synthetic routes outlined
above. An X-ray structure of a potent anthranilic acid
demonstrated that the upper two rings adopt a planar
or nearly planar conformation (Fig. 2). In contrast,
indazol analogs such as 47 (Fig. 1) are twisted out of
plane, providing a hypothesis regarding their reduced
activity relative to the anthranilic acids. Further investi-
gation of the SAR around the acylindazol core and the
B-ring structure with groups designed to favor a planar
conformation may provide access to a more active series
of compounds.
O
NH
O
HN
HN
O
48
Figure 4. X-ray crystal structure of potent anthranilic acid 48.
References and notes
1. Unpublished results and Larsen, S. D.; Hester, M. R.;
Ruble, J. C.; Kamilar, G. M.; Romero, D. L.; Wakefield,
B.; Melchior, E. P.; Sweeney, M. T.; Marotti, K. R.
Bioorg. Med. Chem. Lett. 2006, 16, 6173.
2. Ruble, J. C.; Wakefield, B. D.; Kamilar, G. M.; Marotti,
K. R.; Melchior, E. P.; Sweeney, M. T.; Zurenko, G. E.;
Romero, D. L. Bioorg. Med. Chem. Lett. 2007, 17, 4040.
3. Translation inhibition was demonstrated by using mRNA
(no DNA) in the assay described in Ref. 12.
4. Li, J.; Wakefield, B. D.; Ruble, J. C.; Stiff, C. M.; Romero,
D. L.; Marotti, K. R.; Sweeney, M. T.; Zurenko, G. E.;
Rohrer, D. C.; Thorarensen, A. Bioorg. Med. Chem. Lett.
2007, 17, 2347.
5. Thorarensen, A.; Wakefield, B. D. C. M.; Romero, D. L.;
Marotti, K. R.; Sweeney, M. T.; Zurenko, G. E.; Rohrer,
D. C.; Han, F.; Bryant, G. L. Bioorg. Med. Chem. Lett.
2007, 17, 2823.
methyl substituent and the amide carbonyl may also
cause the twisting. In contrast, anthranilic acids bearing
indole N-1 methyl substitution (Table 1, analogs of
compound 44 or 46) are still highly potent. Modeling
studies support the adoption of a planar conformation
similar to compound 48 likely due to a steric interaction
between the N-methyl indole substituent and the amide
NH. The indazole ring may not provide enough bulk to
bias the conformation. If the out of plane conformation
of the indazols is the cause of their reduced activity rel-
ative to the anthranilic acid counterparts (Fig. 5), future
indazol analogs should be designed with an aryl B-ring
that can intramolcular H-bond to the indazol ring nitro-
gen or to the carbonyl of the amide. This would allow
for the adoption of a planar conformation and subse-
quent proper positioning of the B-ring substituent.
6. Stiff, C. M.; Zhong, M.; Sarver, R. W.; Gao, H.; Ho, A.
M.; Sweeney, M. T.; Zurenko, G. E.; Romero*, D. L.
Bioorg. Med. Chem. Lett. 2007, 17, 2823.
The SAR of the indazol series of analogs deviates from
that of the anthranilic series of analogs in one other way.
Substitution at the 5-position of the anthranilic acid
(corresponding to the 6-position on the indazol) is not
well tolerated,1 whereas in the indazol series the 6-
substituted analogs are equipotent to the 5-substituted
compounds (Table 1, 28 vs 20, 29 vs 23, 30 vs 24). The
indazol upper ring does not overlap exactly with the
anthranilic acid when the southern half of the analog
is held fixed (Fig. 5). This may cause the indazol to ro-
tate or be positioned differently in the binding site allow-
ing for this alternate substitution pattern.
7. Baiocchi, L.; Corsi, G.; Palazzo, G. Synthesis 1978, 633.
8. Anderson, R. J. Chem. Res., Synop. 1985, 376.
9. Compound 26: 1-{3-[(5-chloro-2,3-dihydro-1H-indol-1-
yl)sulfonyl]benzoyl}-5-(trifluoromethoxy)-1H-indazol-3-ol.
Carboxylic acid (337 mg, 1.0 mmol) was placed in a
scintillation vial and suspended in 10 mL of CH2Cl2.
CDI was added (200 mg, 1.25 mmol) and the vial was
capped and agitated for 4 h. Then the indazol (218 mg,
1.0 mmol) was added and the reaction mixture was
allowed to agitate overnight (ꢀ18 h). The reaction mixture
was diluted with 50 mL of CH2Cl2. The organic layer was
washed with 1 N HCl, water, and brine, and dried over
Na2SO4. After concentration, the product was purified by
flash chromatography (1% MeOH in CH2Cl2) affording
403 mg of an off-white solid (75% yield). Analytical sample
obtained by recrystallization from MeOH. 1H NMR
In conclusion, we have discovered that an indazol ring
can serve as a novel anthranilic acid bioisostere. Indaz-