5300
S. Abraham et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5296–5300
NH
N
N
Supplementary data
O
O
O N
HN
H
N
b,c
a
d
HN
O
N
OH
OR
tert
N
OH
OR
N
N
O
Supplementary data associated with this article can be found, in
O
S
18
19
20a
20d R
R
=
=
-
Butyl
17a
R
17d R
=
=
tert-Butyl
C(Me)2CH2CH3
20e R = CH2CH2OCH3
CH(Me)2CH2CH3
17e R = CH2CH2OCH3
References and notes
20f
R
20g R
=
Isopropyl
17f R
=
Isopropyl
1. Marumoto, T.; Zhang, D.; Saya, H. Nat. Rev. Cancer 2005, 5, 42.
2. Giet, R.; Glover, D. M. J. Cell Biol. 2001, 152, 669.
3. Slattery, S. D.; Moore, R. V.; Brinkley, B. R.; Hall, R. M. Cell Cycle 2008, 7,
787.
= Methyl
17g
R
= Methyl
cyclopropyl
20h Cyclopentyl
cyclopropyl
17h
= Cyclopentyl
R
=
R
4. Gautschi, O.; Heighway, J.; Mack, P. C.; Purnell, P. R.; Lara, P. N., Jr.; Gandara, D.
R. Clin. Cancer Res. 2008, 14, 1639.
Scheme 4. Reagents and conditions: (a) mCPBA, DCM, rt, 52%; (b) ROH, B(C6F5)3,
DCM, 90 °C, 5 h; (c) Pd(OH)2, H2, MeOH, ca. 56% over two steps; (d) 11, KI, DIEA,
DMF, 70 °C, 3 h, 23–62%.
5. Pollard, J. R.; Mortimore, M. J. Med. Chem. 2009, 52, 2629.
6. Manfredi, M. G.; Ecsedy, J. A.; Meetze, K. A.; Balani, S. K.; Burenkova, O.; Chen,
W.; Galvin, K. M.; Hoar, K. M.; Huck, J. J.; LeRoy, P. J.; Ray, E. T.; Sells, T. B.;
Stringer, B.; Stroud, S. G.; Vos, T. J.; Weatherhead, G. S.; Wysong, D. R.; Zhang,
M.; Bolen, J. B.; Claiborne, C. F. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 4106.
7. Mortlock, A. A.; Foote, K. M.; Heron, N. M.; Jung, F. H.; Pasquet, G.; Lohmann, J.-
J. M.; Warin, N.; Renaud, F.; De Savi, C.; Roberts, N. J.; Johnson, T.; Dousson, C.
B.; Hill, G. B.; Perkins, D.; Hatter, G.; Wilkinson, R. W.; Wedge, S. R.; Heaton, S.
P.; Odedra, R.; Keen, N. J.; Crafter, C.; Brown, E.; Thompson, K.; Brightwell, S.;
Khatri, L.; Brady, M. C.; Kearney, S.; McKillop, D.; Rhead, S.; Parry, T.; Green, S. J.
Med. Chem. 2007, 50, 2213.
8. Harrington, E. A.; Bebbington, D.; Moore, J.; Rasmussen, R. K.; Ajose-Adeogun,
A. O.; Nakayama, T.; Graham, J. A.; Demur, C.; Hercend, T.; Diu-Hercend, A.; Su,
M.; Golec, J. M. C.; Miller, K. M. Nat. Med. 2004, 10, 262.
9. Mastalerz, H; Trainor, G. L.; Gavai, A. V.; Vyas, D. M. U.S. patent application
2007/4731 A1, 2007.
Table 5
Intravenous rat PK profiles for compounds 1, 9e, 16a, 17a, 17la,b
Compds
Clearance
(mL/min/kg)
Volume of distribution
(L/kg)
Half life
(h)
AUC
MÁh)
(l
1
9e
16a
17a
17l
28.5
53.3
52.2
45
2.15
5.86
9.77
18.3
2.93
10.8
8.66
15.4
11.2
3.36
2.34
0.757
0.581
0.644
1.17
25.2
a
1 mg/kg dosed intravenously.
Sprague Dawley rat, PEG400/water as vehicle.
10. Abraham, S.; Chao, Q.; Hadd, M. J.; Holladay, M. W.; Liu, G.; Nambu, M. D.; Setti,
E. WO201002472, 2010.
b
11. The compounds described herein were tested for their binding affinity to the
catalytic domain of Aurora kinases in a competition binding assay with an ATP-
competitive Aurora inhibitor bound to a solid surface as described in the
following reference: Fabian, M. A.; Biggs, W. H., III; Treiber, D. K.; Atteridge, C.
E.; Azimioara, M. D.; Benedetti, M. G.; Carter, T. A.; Ciceri, P.; Edeen, P. T.; Floyd,
M.; Ford, J. M.; Galvin, M.; Gerlack, J. L.; Grotzfeld, R. M.; Herrgard, S.; Insko, D.
E.; Insko, M. A.; Lai, A. G.; Lelias, J.-M.; Mehta, S. A.; Milanov, Z. V.; Velasco, A.
M.; Wodicka, L. M.; Patel, H. K.; Zarrinkar, P. P.; Lockhart, D. J. Nat. Biotechnol.
2005, 23, 329.
in the study, dosing schedule, strain of animals, and the possibility
of intrinsic toxicity of the lead compounds. Further efforts to im-
prove the overall profiles of the lead compound 17l will be re-
ported in due course.
In summary, introduction of basic amines to the
a-position
of the carboxamide terminus of lead compound 1 resulted in
analogs with high cellular activity and improved rat PK profiles.
Particularly, compound 17l serves as an excellent lead molecule
for further optimization of the overall properties of this series of
pan-Aurora kinase inhibitors.
12. Selectivity score or S(10) is the ratio of kinase targets of the compound to the
total number of kinases screened at a 10 lM compound concentration; kinases
were defined as targets if the primary screen showed >90% competition. See
the following reference for details regarding the calculation of S(10) score:
Karaman, M. W.; Herrgard, S.; Treiber, D. K.; Gallant, P.; Atteridge, C. E.;
Campbell, B. T.; Chan, K. W.; Ciceri, P.; Davis, M. I.; Edeen, P. T.; Faraoni, R.;
Floyd, M.; Hunt, J. P.; Lockhart, D. J.; Milanov, Z. V.; Morrison, M. J.; Pallares, G.;
Patel, H. K.; Pritchard, L. M.; Wodicka, L. M.; Zarrinkar, P. P. Nat. Biotechnol.
2008, 26, 127.
Acknowledgment
13. (a) Schindler, T.; Bornmann, W.; Pellicena, P.; Miller, W. T.; Clarkson, B.;
Kuriyan, J. Science 2000, 289, 1938; (b) Nagar, B.; Bornmann, W. G.; Pellicena,
P.; Schindler, T.; Veach, D. R.; Miller, W. T.; Clarkson, B.; Kuriyan, J. Cancer Res.
2002, 62, 4236.
We thank the KinomeScan group at Ambit Biosciences (now a
division of DiscoveRX) for generating Aurora Kds and kinase spec-
ificity scores.