S. Claridge et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2793–2798
2797
Table 6. The effect of oral dosage of 10a on various human tumor
models in vivo at 20 mg/kg once daily
3. (a) Maulik, G.; Shrikhande, A.; Kijima, T.; Ma, P. C.;
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63, 6272.
Tumor model
Experiment % Tumor growth
duration (days) inhibition
Colo205 (colorectal)
DU145 (prostate)
HCT116 (colorectal)
16
11
14
41
57
41
61
94
MNNGHOS (osteosarcoma) 26
MKN45 (gastric) 13
4. (a) Corso, S.; Comoglio, P. M.; Giordano, S. Trends Mol.
Med. 2005, 11, 284; (b) Comoglio, P. M.; Boccaccio, C.
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Schwall, R.; Ferrara, N.; Gerritsen, M. E. Am. J. Pathol.
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L/(kg h) in dogs. The steady state volume of distribution
was low in rats (0.25 L/kg) and reasonable in dogs
(1.5 L/kg), while the oral bio-availability was deter-
mined to be 12% and 42% in rats and dogs, respectively.
As shown in Table 6, compound 10a performed well in
vivo against a panel of different human tumor types,
particularly those that are driven by or overexpress c-
Met (MNNGHOS and MKN45). Tumor growth inhibi-
tion at a dose of 20 mg/kg po once daily ranged from
41% to 94%. Compound 10a was found to show spill-
over inhibition of a number of kinases in addition to
the intended c-Met/VEGFR2 activity.16 Although dis-
appointing as it was hoped that 10a would be more
selective, the inhibition of multiple kinases could help
with the development of cancer treatments in which tu-
mor growth due to up-regulation of alternative kinase
signaling pathways, occurs. Furthermore, toxicity stud-
ies, using the MDS AdverseReactionEnzymeTM and Hit-
ProfilingTM Assay packages (MDS Pharma) showed that
10a did not exhibit any binding to receptors, channels,
or enzymes that could lead to potential toxicity liabili-
ties. Compound 10a (at 10 lM) did not inhibit
CYP450 3A4, however, it showed some activity against
CYP2C19, and 2DC (data not shown).
7. Peruzzi, B.; Bottaro, D. P. Clin. Cancer Res. 2006, 12,
3657.
8. (a) Fujiwara, A.; Senga, T.; Nishitoba, T.; Osawa, T.;
Miwa, A.; Nakamura, K. PCT Int. Patent Appl. WO
2003/000660; (b) Fujiwara, Y.; Senga, T.; Nishitoba, T.;
Osawa, T.; Nakamura, K. U.S. Patent 2004/0242603; (c)
The additional use of acyl thioureas as inhibitors of c-Met
may be found in the following references: Kung, Pei-Pei
PCT Int. Patent Appl. WO2005/121125; (d) Borzilleri, R.
M.; Chen, Z.; Huynh, T. N.; Vaccaro, W.; Xhen, X. T.;
Kim, K. S.; Cai, Z. W. PCT Int. Patent Appl. WO 2006/
004636; (e) Bannen, L. C.; Chan, D. S.; Dalrymple, L. E.;
Jammalamadaka, V.; Khoury, R. G.; Leahy, J. W.; Mac,
M. B.; Mann, G.; Mann, L. W.; Nuss, J. M.; Parks, J. J.;
Wang, Y.; Xu, W. PCT Int. Patent Appl. WO 2006/
014325.
9. Several compounds using scaffolds other than thieno[3,2-
b]pyridine were synthesized for example thieno[3,2-
b]pyrimidine, pyrrolo[3,2-b]pyridine, purine and pyrrol-
o[3,2-d]pyrimidine but these compounds were far inferior
to the thieno[3,2-b]pyridine in terms of potency. For
details please see Ref. 14.
In conclusion, a series of novel c-Met/VEGFR2 tyrosine
kinase inhibitors based upon the thieno[3,2-b]pyridine
scaffold were designed and synthesized. These com-
pounds exhibited excellent in vitro profiles and in partic-
ular, the most promising compound, 10a, has significant
antitumor activity in vivo. Additional SAR studies have
been undertaken and these will be reported in due
course.
Acknowledgment
10. (a) Barker, J. M.; Huddleston, P. R.; Holmes, D.; Keenan,
G. J.; Wright, B. J. Chem. Res. Miniprint 1984, 771; (b)
Barker, J. M.; Huddleston, P. R.; Holmes, D.; Keenan, G.
J.; Wright, B. J. Chem. Res. Miniprint 1982, 1726.
11. Ragan, J. A.; Raggon, J. W.; Hill, P. D.; Jones, B. P.;
Mcdermott, R. E.; Munchhof, M. J.; Marx, M. A.;
Casavant, J. M.; Cooper, B. A.; Doty, J. L.; Lu, Y. Org.
Process Res. Dev. 2003, 7, 676.
12. Nose, A.; Kudo, T. Chem. Pharm. Bull. 1981, 29, 1159.
13. Smith, P. A. S.; Kan, R. O. J. Org. Chem. 1964, 29, 2261.
14. Vaisburg, A.; Claridge, S. W.; Raeppel, F.; Saavedra, O.
M.; Bernstein, N.; Granger, M.-C.; Zhan, L.; Wahhab, A.;
Llewellyn, D. U.S. Patent 2006/0074056 A1.
We thank Dr. Christiane Maroun for her help in the
preparation of this manuscript.
References and notes
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15. In vitro kinase assays (c-Met and VEGFR-2/KDR):
preparation of GST fusion proteins: recombinant baculo-
2. Birchmeier, C.; Birchmeier, W.; Gherardi, E.; Vande
Woude, G. F. Nat. Rev. Mol. Cell Biol. 2003, 4, 915.