354
M. E. Fraley et al. / Bioorg. Med. Chem. Lett. 14(2004) 351–355
Acknowledgements
Table 5. Pharmacokinetics of 10 and 14 in rat, dog, and monkey
Compd Species Cl (mL/min/kg) t1/2 (h) Vdss (L/kg) Cmax (nM) %F
We thank Matt Zrada and Ken Anderson for logP
determinations and Elaine Walker for assistance in the
preparation of this manuscript.
10
14
10
14
10
14
rata
rata
3.8
29
19
0.5
3.4
12
2.3
1.1
2.4
6.4
2.8
3.4
0.7
0.9
2.9
0.3
0.9
2.1
5790
4800
160
5200
1250
630
31
54
15
63
46
40
dogb
dogb
monkeyb
monkeyb
References and notes
a Mesylate salt dosed 2 mg/kg iv (DMSO), 10 mg/kg po (0.05 M citric
acid).
b Mesylate salt dosed 1 mg/kg iv (DMSO), 1 mg/kg po (0.05 M citric
acid).
1. Adamis, A. P.; Shima, D. T.; Yeo, K. T.; Yeo, T. K.;
Brown, L. F.; Berse, B.; D’Amore, P. A.; Folkman, J.
Biochem. Biophys. Res. Commun. 1993, 193, 631.
2. Giatromanolaki, A.; Sivridis, E.; Athanassou, N.; Zois,
E.; Thorpe, P. E.; Brekken, R. A.; Gatter, K. C.; Harris,
A. L.; Koukourakis, I. M.; Koukourakis, M. I. J. Path.
2001, 194, 101.
3. Enomoto, H.; Inoki, I.; Komiya, K.; Shiomi, T.; Ikeda,
E.; Obata, K.; Matsumoto, H.; Toyama, Y.; Okada, Y.
Am. J. Pathol. 2003, 162, 171.
4. Detmar, M. Dermatol. Sci. 2000, 24, S78.
5. For reviews, see: (a) Carmeliet, P.; Jain, R. K. Nat. 2000,
407, 249. (b) Folkman, J. Nat. Med. 1995, 1, 27.
6. Zetter, B. R. Annu. Rev. Med. 1998, 49, 407.
7. (a) Hanahan, D.; Folkman, J. Cell 1996, 86, 353. (b)
Holmgen, L.; O’Reilly, M. S.; Folkman, J. Nat. Med.
1995, 1, 149.
8. (a) Veikkola, T.; Karkkainen, M.; Claesson-Welsh, L.;
Alitalo, K. Cancer Res. 2000, 60, 203. (b) Thomas, K. A.
J. Biol. Chem. 1996, 271, 603.
9. Kim, K. J.; Li, B.; Winer, J.; Armanini, M.; Gillett, N.;
Phillips, H. S.; Ferrara, N. Nature 1993, 362, 841.
10. Witte, L.; Hicklin, D.; Zhu, Z.; Pytowski, B.; Kotanides,
H.; Rockwell, P.; Bohlen, P. Cancer Metastasis Rev. 1998,
17, 155.
Figure 3. Synthesis of 14.
ment in pharmacokinetics with the 5-sulphoamido lin-
ker came at the expense of decreased KDR kinase
activity and greater binding affinity for hERG. The dif-
ference in hERG activity between the two series may be
related, in part, to their relative lipophilicity; the logP
values of sulphonamides 14 and 15 measured approxi-
mately one-half log unit higher than their direct amide
counterparts 10 and 11.
11. (a) Mendel, D. B.; Laird, A. D.; Xin, X.; Louie, S. G.;
Christensen, J. G.; Li, G.; Schreck, R. E.; Abrams, T. J.;
Ngai, T. J.; Lee, L. B.; Murray, L. J.; Carver, J.; Chan, E.;
¨
Moss, K. G.; Haznedar, J. O.; Sukbuntherng, J.; Blake,
R. A.; Sun, L.; Tang, C.; Miller, T.; Shirazian, S.;
McMahon, G.; Cherrington, J. M. Clin. Cancer Res.
2003, 327. (b) Wedge, S. R.; Ogilvie, D. J.; Dukes, M.;
Kendrew, J.; Chester, R.; Jackson, J. A.; Boffey, S. J.;
Valentine, P. J.; Curwen, J. O.; Musgrove, H. L.; Gra-
ham, G. A.; Hughes, G. D.; Thomas, A. P.; Stokes,
E. S. E.; Curry, B.; Richmond, G. H. P.; Wadsworth,
P. F.; Bigley, A. L.; Hennequin, L. F. Cancer Res. 2002,
62, 4645. (c) Drevs, J.; Hofmann, I.; Hugenschmidt, H.;
The oral pharmacokinetic profiles for compounds 10
and 14 in rat, dog, and monkey are found in Table 5.
Sulphonamide 14 showed greater bioavailability in rat
and dog than did amide 10. That amide 10 exhibited
moderate plasma clearance relative to hepatic blood
flow in the dog suggested that the low bioavailability in
this species was due to a combination of incomplete
absorption and first-pass hepatic elimination.
Wittig, C.; Madjar, H.; Muller, M.; Wood, J.; Martiny-
¨
´
Baron, G.; Unger, C.; Marme, D. Cancer Res. 2000, 60,
4819.
12. Hurwitz, H.; Fehrenbacher, L.; Cartwright, T.; Hains-
worth, J.; Heim, W.; Berlin, J.; Griffing, S.; Novotny, W.;
Holmgren, E.; Kabbinavar, F. Proc. Am. Soc. Clin.
Oncol. 2003, 22; Abstract 3646.
13. For recent reviews, see: (a) Connell, R. D. Expert Opin.
Ther. Pat. 2002, 12, 1763. (b) Boyer, S. J. Curr. Top. Med.
Chem. 2002, 2, 973.
14. (a) Fraley, M. E.; Antanavage, J.; Arrington, K. L.;
Ciecko, P. A.; Coll, K. E.; Gibbs, J. B.; Hambaugh, S. R.;
Hartman, G. D.; Heimbrook, D. C.; Hoffman, W. F.;
Hungate, R. W.; Kohl, N. E.; Mao, X.; McFall, R. C.;
Rands, E.; Rickert, K.; Sepp-Lorenzino, L.; Shipman,
J. M.; Tebben, A. J.; Thomas, K. A. Presented at the
224th National Meeting of the American Chemical
Society, Boston, MA, August 2002; Abstract MEDI-221.
(b) Fraley, M. E.; Hoffman, W. F.; Arrington, K. L.;
Hungate, R. W.; Hartman, G. D.; McFall, R. C.; Coll,
The synthesis of 14 is depicted in Figure 3. Key steps
included the sulfonylation reaction of 1-(tri-
fluoroacetyl)indoline21 and the Suzuki cross-coupling
reaction between the intermediate 2-indolyl boronic
acid and 3-iodo-2-quinolinone22 to furnish the indolyl
quinolinone ring system.
In summary, exchange of the ether linkage in our first
generation KDR kinase inhibitors of the indolyl quino-
linone class for 5-amido and 5-sulfonamido tethers
provided potent compounds that exhibited more favor-
able pharmacokinetic properties and potentially safer
ancillary profiles with lower binding affinity for the IKr
potassiumchannel hERG.