M. Xia et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5964–5968
5967
Table 4. Cyclopentylamine analogs 4
O
R2
N
N
H
R1
Compound
R1
R2
CCR2 binding IC50 (lM)
4a (cis-Racemate)
4b (cis-Racemate)
4-Methoxy
4-Methoxy
4-Methoxy
4-Methoxy
4-Methoxy
4-Methoxy
4-Methoxy
4-Methoxy
4-Methoxy
4-Methoxy
3,4-Difluoro
3,4-Dichloro
3,5-Dichloro
3,5-Dichloro
3,5-Dichloro
3,5-Difluoro
3,5-Difluoro
3,5-Difluoro
3,4,5-Trifluoro
3,4,5-Trifluoro
3,4,5-Trifluoro
3,5-Difluoro
0.14
0.18
0.16
6.45
0.24
0.16
4c (1S,3R-Enantiomer)
4d (1R,3S-Enantiomer)
4e (cis-Racemate)
4f (1S,3R-Enantiomer)
4g (1R,3S-Enantiomer)
4h (cis-Racemate)
12.0
0.13
0.08
8.40
0.79
4i (1S,3R-Enantiomer)
4j (1R,3S-Enantiomer)
4k (cis-Racemate)
R
S
S
R
17. Brodmerkel, C. M.; Huber, R.; Covington, M.; Diamond,
S.; Hall, L.; Collins, R.; Leffet, L.; Gallagher, K.;
Feldman, P.; Collier, P.; Stow, M.; Gu, X.; Baribaud,
F.; Shin, N.; Thomas, B.; Burn, T.; Hollis, G.; Yeleswa-
ram, S.; Solomon, K.; Friedman, S.; Wang, A.; Xue, C. B.;
Newton, R. C.; Scherle, P.; Vaddi, K. J. Immunol. 2005,
175, 5370.
N
N
NH
O
NH
R
R
Ar
Ar
O
Figure 2. Cyclopentylamine diastereomers.
18. Van Lommen, G.; Doyon, J.; Coesemans, E.; Boeckx, S.;
Cools, M.; Buntinx, M.; Hermans, B.; Van Wauwe, J.
Bioorg. Med. Chem. Lett. 2005, 15, 497.
for these bioavailable CCR2 antagonists will be the sub-
ject of a future publication.
19. Imai, M.; Shiota, T.; Kataoke, K.; Tarby, C.; Moree, W.;
Tsutsumi, T.; Sudo, M.; Ramirez-Weinhouse, M.; Comer,
D.; Sun, C. M.; Yamagami, S.; Tanaka, H.; Morita, T.;
Hada, T.; Greene, J.; Barnum, D.; Saunders, J.; Myers, P.;
Kato, Y.; Endo, N. Bioorg. Med. Chem. Lett. 2004, 14,
5407.
20. Moree, W.; Kataloka, K.; Ramirez-Weinhouse, M.; Shi-
ota, T.; Imai, M.; Sudo, M.; Tsutsumi, T.; Endo, N.;
Muroga, Y.; Hada, T.; Tanaka, H.; Morita, T.; Greene, J.;
Barnum, D.; Saunders, J.; Kato, Y.; Myers, P.; Tarby, C.
Bioorg. Med. Chem. Lett. 2004, 14, 5413.
References and notes
1. Gerard, C.; Rollins, B. J. Nat. Immunol. 2001, 2, 108.
2. Luther, S. A.; Crster, J. G. Nat. Immunol. 2001, 2, 102.
3. Murphy, P. M.; Baggiolini, M.; Charo, I. F.; Hebert, C.
A.; Horuk, R.; Matsushima, K.; Miller, L. H.; Oppen-
heim, J. J.; Power, C. A. Pharmacol. Rev. 2000, 52, 145.
4. Gu, L.; Tseng, S. C.; Rollins, B. J. Chem. Immunol. 1999,
72, 7.
5. Charo, I. F.; Myers, S. J.; Herman, A.; Franci, F.;
Connolly, A. J.; Coughlin, S. R. Proc. Natl. Acad. Sci.
U.S.A. 1994, 91, 2752.
6. Kurihara, T.; Warr, G.; Loy, J.; Bravo, R. J. Exp. Med.
1997, 186, 1757.
7. Boring, L.; Gosling, J.; Chensue, S. W.; Kunkel, S. L.;
Farese, R. V., Jr.; Broxmeyer, H. E.; Charo, I. F. J. Clin.
Invest. 1997, 100, 2552.
8. Carulli, M. T.; Ong, V. H.; Ponticos, M.; Xu, S.;
Abraham, D. J.; Black, C. M.; Denton, C. P. Arthritis
Rheum. 2005, 52, 3772.
21. Witherington, J.; Bordas, V.; Cooper, D. G.; Forbes, I. T.;
Gribble, A. D.; Ife, R. J.; Berkhout, T.; Gohil, J.; Groot,
P. H. E. Bioorg. Med. Chem. Lett. 2001, 11, 2177.
22. Forbes, I. T.; Cooper, D. G.; Dodds, E. K.; Hickey, D. M.
B.; Ife, R. J.; Meeson, M.; Stockley, M.; Berkhout, T. A.;
Gohil, J.; Groot, P. H. E.; Moores, K. Bioorg. Med. Chem.
Lett. 2000, 10, 1803.
23. Mirzadegan, T.; Diehl, F.; Ebi, B.; Bhakta, S.; Polsky, I.;
McCarley, D.; Mulkins, M.; Weatherhead, G. S.; Lapi-
erre, J. M.; Dankwardt, J.; Morgans, D.; Wilhelm, R.;
Jarnagin, K. J. Biol. Chem. 2000, 275, 25562.
9. Weisberg, S. P.; Hunter, D.; Huber, R.; Lemieux, J.;
Slaymaker, S.; Vaddi, K.; Charo, I.; Leibel, R. L.;
Ferrante, A. W., Jr. J. Clin. Invest. 2006, 116, 115.
10. Charo, I. F.; Taubman, M. B. Circ. Res. 2004, 95,
858.
11. Kitagawa, K.; Wada, T.; Furuichi, K.; Hashimoto, H.;
Ishiwata, Y.; Asano, M.; Takeya, M.; Kuziel, W. A.;
Matsushima, K.; Mukaida, N.; Yokoyama, H. Am. J.
Pathol. 2004, 165, 237.
12. Dawson, J.; Miltz, W.; Mir, A. K.; Wiessner, C. Expert
Opin. Ther. Targets 2003, 7, 35.
13. Gongh, J. H.; Ratkay, L. G.; Waterfield, J. D.; Clark-
Lewis, I. J. Exp. Med. 1997, 186, 131.
24. Shiraishi, M.; Aramaki, Y.; Seto, M.; Imoto, H.; Nishik-
awa, O.; Kanzaki, N.; Okamoto, M.; Sawada, H.;
Nishimura, O.; Baba, M.; Fujino, M. J. Med. Chem.
2000, 43, 2049.
25. The binding affinities were evaluated in THP-1 cells. THP-
1 cells were incubated with 0.5 nM 125I labeled MCP-1
(Perkin-Elmer Life Sciences, Inc., Boston, MA) in the
presence of varying concentrations of either unlabeled
MCP-1 (R&D Systems, Minneapolis, MN) or test com-
pound for 2 h at 30 ꢁC in a 96-well plate. Cells were then
harvested onto a filter plate, dried, and 20 lL of Micro-
scint 20 was added to each well. Plates were counted in a
TopCount NXT, Microplate Scintillation & Luminescence
Counter (Perkin-Elmer Life Sciences, Inc., Boston, MA).
Blank values (buffer only) were subtracted from all values
and drug treated values were compared to vehicle treated
values. One micromolar cold MCP-1 was used for non-
14. Izikson, L.; Klein, R. S.; Luster, A. D.; Weiner, H. L. Clin.
Immunol. 2002, 103, 125.
15. Ross, R. New Engl. J. Med. 1999, 147, 213.
16. Donnelly, L. E.; Duncan, F. R. Drugs 2003, 63, 1973.