4912
P. Ballard et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4908–4912
6. Hennequin, L. F.; Stokes, E. S. E.; Thomas, A. P.;
impact of these changes. Female nude mice were
implanted subcutaneously with 1 · 107 LoVo colon
tumour cells. Once tumours were established, animals
were randomised between groups (n = 7 per group)
and dosed po with compound suspended in 1% (v/v)
polysorbate 80. Table 6 indicates the efficacy and
exposure of compound 20 in this study, alongside 1
for comparative purposes. As expected, gefitinib 1
shows good activity and clear dose–response at 50
and 100 mg/kg doses. Compound 20 shows compara-
ble activity at 50 mg/kg, although appears less
efficacious at the higher dose of 100 mg/kg, despite
linear increases in exposure over the dose range.
However, consistent with the shorter half-life for this
´
Johnstone, C.; Ple, P. A.; Ogilvie, D. J.; Dukes, M.;
Wedge, S. R.; Kendrew, J.; Curwen, J. O. J. Med. Chem.
2002, 45, 1300.
7. Heymach, J. V. Br. J. Cancer 2005, 92(Suppl.1), S14.
8. McKillop, D.; Partridge, E. A.; Hutchison, M.; Rhead, S.
A.; Parry, A. C.; Bardsley, J.; Woodman, H. M.; Swais-
land, H. C. Xenobiotica 2004, 34, 901.
9. Swaisland, H.; Laight, A.; Stafford, L.; Jones, H.; Morris,
C.; Dane, A.; Yates, R. Clin. Pharmacokinet. 2001, 40,
297.
10. Tiseo, M.; Loprevite, M.; Ardizzoni, A. Curr. Med.
Chem.—Anti-Cancer Agents 2004, 4, 139.
11. Ranson, M.; Hammond, L. A.; Ferry, D.; Kris, M.; Tullo,
A.; Murray, P. I.; Miller, V.; Averbuch, S.; Ochs, J.;
Morris, C.; Feyereislova, A.; Swaisland, H.; Rowinsky, E.
K. J. Clin. Oncol. 2002, 20, 2240.
compound, dosing twice
a day results in 91%
inhibition of tumour volume relative to control
animals, substantially better than once a day dosing,
including at 100 mg/kg.
12. Miller, K. D.; Trigo, J. M.; Wheeler, C.; Barge, A.;
Rowbottom, J.; Sledge, G.; Baselga, J. Clin. Cancer Res.
2005, 11, 3369.
13. Undevia, S. D.; Gomez-Abuin, G.; Ratain, M. J. Nat. Rev.
Cancer 2005, 5, 447.
14. Barker, A. J.; Gibson, K. H.; Grundy, W.; Godfrey, A. A.;
Barlow, J. J.; Healy, M. P.; Woodburn, J. R.; Ashton, S.
E.; Curry, B. J.; Scarlett, L.; Henthorn, L.; Richards, L.
Bioorg. Med. Chem. Lett. 2001, 11, 1911.
15. Compounds were evaluated in an EGFR kinase assay
measuring inhibition of phosphorylation of a synthetic
peptide substrate at Km ATP concentration. Inhibition of
proliferation of KB cells in response to EGF stimulus was
also assessed. For details of assay conditions see, Henne-
quin, L. F. A.; Kettle, J. G.; Pass, M.; Bradbury, R. H.
PCT Int. Appl. WO2003040109.
In summary, in the compounds tested aniline and side-
chain structural modifications to the EGFR inhibitory
anilinoquinazoline template gave substantial increases
in enzyme and cellular potencies. These changes in com-
bination with side-chain pKa modulation have led to
compounds with a markedly altered pharmacokinetic
profile, which nevertheless show profound inhibition
of tumour growth in a selected disease model.
References and notes
16. The rat pharmacokinetic data reported in this paper are
from a protocol designed to allow high throughput
profiling of compounds and as such are non-optimised.
Literature data for 1 (see Ref. 8) show some variance with
the data in Table 2 due to the more detailed nature, and
differing protocols used in these studies.
1. Hynes, N. E.; Lane, H. A. Nat. Rev. Cancer 2005, 5, 341.
2. Cohen, M. H.; Williams, G. A.; Sridhara, R.; Chen, G.;
McGuinn, W. D., Jr.; Morse, D.; Abraham, S.; Rahman,
A.; Liang, C.; Lostritto, R.; Baird, A.; Pazdur, R. Clin.
Cancer Res. 2004, 10, 1212.
17. While the clearance figure of 129 ml/min/kg is seemingly at
odds with the reported bioavailability of 74%, it should be
noted that this is for clearance of drug from plasma. This
basic compound partitions extensively into blood, such
that the blood clearance is a more realistic 65 ml/min/kg.
Nevertheless, the good bioavailability observed may
reflect saturation of first-pass clearance, or other non-
hepatic routes of elimination.
3. Ple, P. A.; Green, T. P.; Hennequin, L. F.; Curwen, J.;
Fennell, M.; Allen, J.; Lambert-van der Brempt, C.;
Costello, G. J. Med. Chem. 2004, 47, 871.
4. Mortlock, A. A; Keen, N. J.; Jung, F. H.; Brewster, A. G.
PCT Int. Appl. WO 2001021596.
5. Shewchuk, L.; Hassell, A.; Wisely, B.; Rocque, W.;
Holmes, W.; Veal, J.; Kuyper, L. F. J. Med. Chem.
2000, 43, 133.