H. Tajima et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1232–1235
1235
E.; Roth, R.; Schlachter, C.; Vetterli, W.; Wyss, D.; Wood, J. J. Med. Chem. 2000,
43, 3200.
In conclusion, we designed, synthesized, and evaluated the no-
vel 4-pyridylmethylthio derivatives from compounds 5 and 6 to
discover effective VEGF inhibitors and reduce CYP inhibition activ-
ity. As a result, we found N-oxide derivative 7 and 2-substituted
pyridine derivatives (like 10g) showed activities in the cell based
assay (VEGF induced HUVEC proliferation assay), and the CYP inhi-
bition activities were reduced. Among these compounds, 10g was
highly active and hydrophilic. Moreover it showed efficacies in
all three animal models: xenograft model reflecting cancer, rat
adjuvant arthritis model revealing the RA, and rat laser induced
CNV model known as the indicating model of AMD. These results
suggested that compound 10g had favorable potency for drugs
against the above mentioned diseases.
8. (a) Manley, P. W.; Furet, P.; Bold, G.; Brueggen, J.; Mestan, J.; Meyer, T.; Schnell,
C. R.; Wood, J. J. Med. Chem. 2002, 45, 5687; (b) Manley, P. M.; Bold, G.; Brüggen,
J.; Fendrich, G.; Furet, P.; Mestan, J.; Schnell, C.; Stolz, B.; Meyer, T.; Meyhack,
B.; Stark, W.; Strauss, A.; Wood, J. Biochim. Biophys. Acta, Proteins Proteomics
2004, 1697, 17.
9. Polverino, A.; Coxon, A.; Starnes, C.; Diaz, Z.; DeMelfi, T.; Wang, L.; Bready, J.;
Estrada, J.; Cattley, R.; Kaufman, S.; Chen, D.; Gan, Y.; Kumar, G.; Meyer, J.;
Neervannan, S.; Alva, G.; Talvenheimo, J.; Montestruque, S.; Tasker, A.; Patel, V.;
Radinsky, R.; Kendall, R. Cancer Res. 2006, 66, 8715.
10. (a) Honda, T.; Tajima, H.; Kaneko, Y.; Ban, M.; Inaba, T.; Takeno, Y.; Okamoto,
K.; Aono, H. Bioorg. Med. Chem. Lett. 2008, 18, 2939; (b) Tajima, H.; Honda, T.;
Kawashima, K.; Sasabuchi, Y.; Yamamoto, M.; Ban, M.; Okamoto, K.; Inoue, K.;
Inaba, T.; Takeno, Y.; Aono, H. Bioorg. Med. Chem. Lett. 2010, 20, 7234.
11. Bohlmann, R.; Haberey, M.; Huth, A.; Ince, S. J.; Krueger, M.; Thierauch, K.-H.;
Hess-Stumpp, H.; US Patent/US 7572794, 2005.
12. Wermuth, C. G. The Practice of Medicinal Chemistry, 2nd ed.; Elsevier, 1990.
Chapter 30.
Supplementary data
13. (a) Laufer, S. A.; Wagner, G. K.; Kotschenreuther, D. A.; Albrecht, W. J. Med.
Chem. 2003, 46, 3230; (b) Shi, T.; Lia, C.; O’Connora, S. P.; Zhang, J.; Shi, M.;
Bisahaa, S. N.; Wanga, Y.; Sitkoffa, D. S.; Pudzianowskia, A. T.; Huanga, C.; Kleia,
H. E.; Kisha, K.; Yanchunas, J., Jr.; Liua, E. C. K.; Hartla, K. S.; Seilera, S. M.;
Steinbachera, T. E.; Schumachera, A. W.; Atwala, K. S.; Steina, P. D. Bioorg. Med.
Chem. Lett. 2009, 19, 6882.
Supplementary data associated with this article can be found, in
14. (a) Annie, T.; Fong, T.; Shawver, L. K.; Sun, L.; Tang, C.; App, H.; Powell, T. J.;
Kim, Y. H.; Schreck, R.; Wang, X.; Risau, W.; Ullrich, A.; Hirth, K. P.; McMahon,
G. Cancer Res.. 1999, 59, 99; (b) HUVEC was cultured into collagen coated well
plate. After 1 day of incubation, VEGF and a test compound were added. After
3 days of incubation, cell number was counted. Compared with control, cell
growth rate was calculated; see also Supplementary data.
15. (a) Prewett, M.; Huber, J.; Li, Y.; Santiago, A.; O’Connor, W.; King, K.;
Overholser, J.; Hooper, A.; Pytowski, B.; Witte, L.; Bohlen, P.; Hicklin, D. J.
Cancer Res. 1999, 59, 5209; (b) B16 cell suspension was sc injected into the
C57BL/6 mouse (female, six weeks old) under anesthesia. The suspension of a
test compound was administrated orally once a day every day. Ten days after
injection, the weight of extirpated tumor tissue was measured. Compared with
control, anti-cancer effect was calculated; see also Supplementary data.
16. The adjuvant was injected subcutaneously into a left hind paw sole of Lewis
rats (male, nine weeks old) to induce arthritis. The suspension of a test
compound was administrated orally once a day every day. Twenty one days
after induction, the paw volume was measured. Paw edema inhibition rate was
calculated and compared with control; see also Supplementary data.
17. (a) Xianjin, X.; Ogata, N.; Komada, M.; Yamamoto, C.; Takahashi, K.; Omori, K.;
Uyama, M. Graefes Arch. Cli. Exp. Ophthalmol. 1997, 235, 313; (b) Under
References and notes
1. (a) Shibuya, M. Folia Pharmacol. Japonica 2003, 122, 498; (b) Sone, H.;
Kawakami, Y.; Sakauchi, M.; Nakamura, Y.; Takahashi, A.; Shimano, H.;
Okuda, Y.; Segawa, T.; Suzuki, H.; Yamada, N. Biochem. Biophys. Res. Commun.
2001, 281, 562; (c) Kvanta, A.; Algvere, P. V.; Berglin, L.; Seregard, S. Invest.
Ophthalmol. Vis. Sci. 1996, 37, 1929.
2. Bell, C.; Lynam, E.; Landfair, D. J.; Janjic, N.; Wiles, M. E. In Vitro Cell Dev. Biol.
Anim. 1999, 35, 533.
3. Chen, Y.; Wiesmann, C.; Fuh, G.; Li, B.; Christinger, H. W.; McKay, P.; de Vos, A.
M.; Lowman, H. B. J. Mol. Biol. 1999, 293, 865.
4. Lin, Y. S.; Nguyen, C.; Mendoza, J. L.; Escandon, E.; Fei, D.; Meng, Y. G.; Modi, N.
B. J. Pharmacol. Exp. Ther. 1999, 288, 371.
5. Sun, L.; Liang, C.; Shirazian, S.; Zhou, Y.; Miller, T.; Cui, J.; Fukuda, J. Y.; Chu, J. Y.;
Nematalla, A.; Wang, X.; Chen, H.; Sistla, A.; Luu, T. C.; Tang, F.; Wei, J.; Tang, C.
J. Med. Chem. 2003, 46, 1116.
6. Harris, P. A.; Boloor, A.; Cheung, M.; Kumar, R.; Crosby, R. M.; Davis-Ward, R. G.;
Epperly, A. H.; Hinkle, K. W.; Hunter, R. N., 3rd; Johnson, J. H.; Knick, V. B.;
Laudeman, C. P.; Luttrell, D. K.; Mook, R. A.; Nolte, R. T.; Rudolph, S. K.;
Szewczyk, J. R.; Truesdale, A. T.; Veal, J. M.; Wang, L.; Stafford, J. A. J. Med. Chem.
2008, 51, 4632.
7. (a) Bold, G.; Altmann, K. H.; Jorg, F.; Lang, M.; Manley, P. W.; Traxler, P.;
Wietfeld, B.; Bruggen, J.; Buchdunger, E.; Cozens, R.; Ferrari, S.; Furet, P.;
Hofmann, F.; Martiny-Baron, G.; Mestan, J.; Rosel, J.; Sills, M.; Stover, D.; Masso,
E.; Roth, R.; Schlachter, C.; Vetterli, W.; Wyss, D.; Wood, J. J. Med. Chem. 2000,
43, 2310; (b) Bold, G.; Altmann, K. H.; Jorg, F.; Lang, M.; Manley, P. W.; Traxler,
P.; Wietfeld, B.; Bruggen, J.; Buchdunger, E.; Cozens, R.; Ferrari, S.; Pascal, F.;
Hofmann, F.; Martiny-Baron, G.; Mestan, J.; Rosel, J.; Sills, M.; Stover, D.; Masso,
anesthesia and mydriasis, photocoagulation was performed in
a Bruch’s
membrane of Brown Norway rats (male, eight weeks old) with a krypton
laser. The suspension of a test compound was administrated orally once a day
every day. Seven days after photocoagulation, fluorescein solution was injected
into
a tail vein. After fluorescein fundus photography was performed,
fluorescence leak was counted. Neovascularization incidence rate was
calculated and compared with control; see also Supplementary data.