M. G. Saulnier et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1702–1707
1707
tumor cells in which the PI3K/AKT pathway is constitu-
tively activated and the p53 pathway is functional. See
Fujiwara, Y.; Kawada, K.; Takano, D.; Tanimura, S.;
Ozaki, K.; Kohno, M. Biochem. Biophys. Res. Commun.
2006, 340, 560.
G.; Ruetz, S.; Hofmann, F. Cancer Cell 2004, 5, 231; (c)
Blum, G.; Gazit, A.; Levitzki, A. J. Biol. Chem. 2003, 278,
40442; (d) Girnita, A.; Girnita, L.; del Prete, F.; Bart-
olazzi, A.; Larsson, O.; Axelson, M. Cancer Res. 2004, 64,
236; (e) Mulvihill, M. J.; Ji, Q.-S.; Werner, D.; Beck, P.;
Cesario, C.; Cooke, A.; Cox, M.; Crew, A.; Dong, H.;
Feng, L.; Foreman, K. W.; Mak, G.; Nigro, A.; O’Con-
nor, M.; Saroglou, L.; Stolz, K. M.; Sujka, I.; Volk, B.;
Weng, Q.; Wilkes, R. Bioorg. Med. Chem. Lett. 2007, 17,
1091.
5. There is evidence that antidiabetic drugs, such as the
PPARc agonist thiazolidinedione, rosiglitazone, suppress
IGF-1 tumor-promoting activity. See He, G.; Sung, Y. M.;
DiGiovanni, J.; Fischer, S. M. Cancer Res. 2006, 66, 1873.
6. (a) Wittman, M.; Carboni, J.; Attar, R.; Balasubramani-
an, B.; Balimane, P.; Brassil, P.; Beaulieu, F.; Chang, C.;
Clarke, W.; Dell, J.; Eummer, J.; Frennesson, D.;
Gottardis, M.; Greer, A.; Hansel, S.; Hurlburt, W.;
Jacobson, B.; Krishnananthan, S.; Lee, F. Y.; Li, A.;
Lin, T.-A.; Liu, P.; Ouellet, C.; Sang, X.; Saulnier, M.;
Stoffan, K.; Sun, Y.; Velaparthi, U.; Wong, H.; Yang, Z.;
Zimmermann, K.; Zoeckler, M.; Vyas, D. J. Med. Chem.
2005, 48, 5639; (b) Carboni, J. M.; Lee, A. V.; Hadsell, D.
L.; Rowley, B. R.; Lee, F. Y.; Bol, D. K.; Camuso, A. E.;
Gottardis, M.; Greer, A. F.; Ho, C. P.; Hurlburt, W.; Li,
A.; Saulnier, M. G.; Velaparthi, U.; Wang, C.;
Wen, M.-L.; Westhouse, R. A.; Wittman, M.; Zimmer-
mann, K.; Rupnow, B. A.; Wong, T. W. Cancer Res. 2005,
65, 3781; (c) Haluska, P.; Carboni, J. M.; Loegering, D.
A.; Lee, F. Y.; Wittman, M.; Saulnier, M. G.; Frennesson,
D. B.; Kalli, K. R.; Conover, C. A.; Attar, R. M.;
Kaufmann, S. H.; Gottardis, M.; Erlichman, C. Cancer
Res. 2006, 66, 362; (d) Wittman, M.; Balasubramanian, B.;
Stoffan, K.; Velaparthi, U.; Liu, P.; Krishnananthan, S.;
Carboni, J.; Li, A.; Greer, A.; Attar, R.; Gottardis, M.;
Chang, C.; Jacobson, B.; Sun, Y.; Hansel, S.; Zoeckler,
M.; Vyas, D. Bioorg. Med. Chem. Lett. 2007, 17, 974; (e)
Velaparthi, U.; Wittman, M.; Liu, P.; Stoffan, K.; Zim-
mermann, K.; Sang, X.; Carboni, J.; Li, A.; Attar, R.;
Gottardis, M.; Greer, A.; Chang, C.; Jacobson, B.; Sack,
J.; Sun, Y.; Langley, D. R.; Balasubramanian, B.; Vyas,
D. Bioorg. Med. Chem. Lett. 2007, 17, 2317; (f) Velaparthi,
U.; Liu, P.; Balasubramanian, B.; Carboni, J.; Attar, R.;
Gottardis, M.; Li, A.; Greer, A.; Zoeckler, M.; Wittman,
M.; Vyas, D. Bioorg. Med. Chem. Lett. 2007, 17, 3072.
7. Other small molecule inhibitors of IGF-1R have been
reported which show in vivo antitumor activity in animal
models. See, (a) Mitsiades, C. S.; Mitsiades, N. S.;
McMullan, C. J.; Poulaki, V.; Shringarpure, R.; Akiyama,
M.; Hideshima, T.; Chauhan, D.; Joseph, M.; Libermann,
T. A.; Garcia-Echeverria, C.; Pearson, M. A.; Hofmann,
F.; Anderson, K. C.; Kung, A. L. Cancer Cell 2004, 5, 221;
(b) Garcia-Echeverria, C.; Pearson, M. A.; Marti, A.;
Meyer, T.; Mestan, J.; Zimmermann, J.; Gao, J.; Brueg-
gen, J.; Capraro, H. G.; Cozens, R.; Evans, D. B.; Fabbro,
D.; Furet, P.; Porta, D. G.; Liebetanz, J.; Martiny-Baron,
8. The 2-(1,2,3-triazol-4-yl)ethanamine and 2-(thiazol-4-
yl)ethanamine side chain analogs of 1 are 3- and 4-fold
less potent toward IGF-1R than 1, respectively. In a
related series, the 1-methyl histamine analog has the same
IGF-1R potency and also shows about 5-fold better
cellular potency than the analog derived from histamine
itself.
9. (a) Durant, G. J.; Emmett, J. C.; Ganellin, C. R.; Roe,
A. M.; Slater, R. A. J. Med. Chem. 1976, 19, 923; (b)
Jain, R.; Cohen, L. A. Tetrahedron 1996, 52, 5363; (c)
Jain, R.; Avramovitch, B.; Cohen, L. A. Tetrahedron
1998, 54, 3235; (d) Narayanan, S.; Vangapandu, S.; Jain,
R. Bioorg. Med. Chem. Lett. 2001, 11, 1133; (e) Collman,
J. P.; Zhong, M.; Costanzo, S. J. Chem. Res. (S) 2001,
195.
10. Yu and Macor also report mono-chlorination of an
electron-rich heterocycle (thiophene) in the presence on
an unprotected primary amine. See Yu, G.; Mason, H. J.;
Galdi, K.; Wu, X.; Cornelius, L.; Zhao, N.; Witkus, M.;
Ewing, W. R.; Macor, J. E. Synthesis 2003, 3, 403.
11. For relevant references for such Cu(I)-catalyzed coupling
reactions, see (a) Wu, Y.-J.; He, H. Synlett 2003, 12, 1789;
(b) Wu, Y.-J.; He, H.; L’Heureux, A. Tetrahedon Lett.
2003, 44, 4217; (c) Antilla, J. C.; Baskin, J. M.; Barder, T.
E.; Buchwald, S. L. J. Org. Chem. 2004, 69, 5578.
12. Saulnier, M. G.; Zimmermann, K.; Struzynski, C. P.;
Sang, X.; Velaparthi, U.; Wittman, M.; Frennesson, D. B.
Tetrahedon Lett. 2004, 45, 397.
13. Fatin-Rouge, N.; Toth, E.; Perret, D.; Backer, R. H.;
Merbach, A. E.; Bunzli, J.-C. G. J. Am. Chem. Soc. 2000,
122, 10810.
14. Oral exposure (0–4 h AUC) was determined by dosing
mice at 20 mg/kg. For details, see Ref. 6a.
15. Note, the coupled products of 7o–p with 15 are only weak
inhibitors of IGF-1R (data not shown).
16. The utility of the 17f chloropyrazole side chain in a related
series of benzimidazoles will be the subject of future
reports from our laboratories. Whereas the oral exposure
data were not obtained for 4-bromopyrazole 17g, the
advantages of 4-chloro over 4-bromopyrazoles in these
related series will also be reported therein.