J. G. Kettle et al. / Bioorg. Med. Chem. Lett. 14 (2004) 405–408
Table 3. Effect of substitution on the indole ring of compound 5
407
Compd
2b IC
RCCR
H
(mM)
50
Scheme 1. Reagents and conditions: (a) CH3COCO2Et, EtOH,
AcOH; (b) polyphosphoric acid, 90 ꢀC; (c) ZnCl2, AcOH, reflux;
(d) NaH, DMF, R-PhCH2Cl; (e) 3 M NaOH, THF, EtOH.
5
0.23
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
4-NO2
1.31
0.39
1.64
10.84
1.19
0.17
1.05
1.27
3.88
2.2
0.099
0.056
0.09
0.125
0.26
0.15
0.11
0.34
0.34
0.77
0.28
0.41
2.3
5-NO2
6-NO2
7-NO2
4-CF3
5-CF3
6-CF3
7-CF3
4-SO2CH3
5-SO2CH3
4-F
5-F
6-F
7-F
3-Cl
4-Cl
5-Cl
6-Cl
7-Cl
3-OCH3
4-OCH3
5-OCH3
6-OCH3
7-OCH3
4-NH2
5-NH2
6-NH2
4-Ph
5-Ph
6-Ph
3-CN
3-COOH
Regioisomers were separated at this stage via column
chromatography or crystallization. The indoles were
then alkylated with benzyl halides following deprotona-
tion with sodium hydride, and the target compounds
obtained upon saponification. 3-Substituted indoles
were generally prepared by derivation of indole deriva-
tives prior to benzylation using standard procedures.38
References and notes
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1.21
0.23
0.5
12.6
0.64
8.6
12.3
0.30
0.096
9. Koch, A. E.; Kunkel, S. L.; Harlow, L. A.; Johnson, B.;
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The optimal indole substituent found in this study was
the 5-fluoro group, which had an IC50 of 56 nM (com-
pound 33). The ability of this compound to inhibit chemo-
taxis of cells expressing CCR2b receptor in response to
an MCP-1 stimulus was examined, and an IC50 of
312 nM observed for inhibition of this response.37 In
addition, representative compounds were further pro-
filed against a panel of over 40 other seven-transmem-
brane G-protein coupled receptor binding assays. These
included a and b adrenoceptors, 5-HT and muscarinic
receptors, and ion channels. All compounds had IC50
values greater than 10 mM. Thus, the N-benzylindole-2-
carboxylic acids represent a novel class of potent, selec-
tive and functionally active inhibitors of the CCR2b
chemokine receptor.
14. Kurashima, K.; Mukaida, N.; Fujimura, M.; Schroder, J-
¨
M.; Matsuda, T.; Matsushima, K. J. Leukocyte Biol.
1996, 59, 313.
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16. Sousa, A. R.; Lane, S. J.; Nakhosteen, J. A.; Yoshimura,
T.; Lee, T. H.; Poston, R. N. Am. J. Respir. Cell Mol.
Biol. 1994, 10, 142.
2.Chemistry
The compounds described herein were synthesized
according to the generic route shown in Scheme 1.
Indole-2-carboxylic esters were either purchased from
commercial sources, or isolated following Fischer indo-
lization of the ethyl pyruvate hydrazones shown.
17. Gillitzer, R.; Wolff, K.; Tong, D.; Muller, C.; Yoshimura,
¨
T.; Hartmann, A. A.; Stingl, G.; Berger, R. J. Invest.
Dermatol. 1993, 101, 127.
18. Kristensen, M. S.; Deleuran, B. W.; Larsen, C. G.;