Letters
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 13 4211
(8) Misra, R. N.; Xiao, H.; Kim, K. S.; Lu, S.; Han, W.; Barbosa, S.
A.; Hunt, J. T.; Rawlins, D. B.; Shan, W.; Ahmed, S. J.; Qian,
L.; Chen, B.; Zhao, R.; Bednarz, M. S.; Kellar, K. A.; Mulheron,
J. G.; Batorsky, R.; Roongta, U.; Kamath, A.; Marathe, P.;
Ranadive, S. A.; Sack, J. S.; Tokarski, J. S.; Pavletich, N. P.;
Lee, F. Y. F.; Webster, K. R.; Kimball, S. D. N-(Cycloalkylamino)-
acyl-2-aminothiazole inhibitors of cyclin-dependent kinase 2.
N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-
4-piperidinecarboxamide (BMS-387032), a highly efficacious and
selective antitumor agent. J. Med. Chem. 2004, 47, 1719.
(9) Toogood, P. L.; Harvey, P. J.; Repine, J. T.; Sheehan, D. J.;
VanderWel, S. N.; Zhou, H.; Keller, P. R.; McNamara, D. J.;
Sherry, D.; Zhu, T.; Brodfuehrer, J.; Choi, C.; Barvian, M. R.;
Fry, D. W. Discovery of a potent and selective inhibitor of cyclin-
dependent kinase 4/6. J. Med. Chem. 2005, 48, 2388.
(10) (a) Chong, W. K.; Chu, S. S.; Duvadie, R. R.; Li, L.; Xiao, W.;
Yang, Y. 4-Aminothiazole derivatives, their preparation and
their use as inhibitors of cyclin-dependent kinases. PCT Appl.
WO 9921845, 1999. (b) Li, L.; Duvadie, R. K.; Chong, W. K. M.;
Chu, S. S.; Yang, Y.; Nonomiya, J.; Tucker, K. D.; Lewis, C. T.;
Knighton, D. R.; Ferre, R. A.; Lundgren, K.; Koudriakova, T.;
Escobar, J.; Minnick P.; Price, S. M.; Huber, A.; Sisson, W.; Aust,
R. M.; Verkhivker, G. M.; Schaffer, L.; Rose, P. W. Novel ATP-
site cyclin-dependent kinase (CDK) inhibitors: Selective inhibi-
tors of CDK4/cyclin D. Book of Abstracts, 218th National Meeting
of the American Chemical Society: New Orleans, LA, August
22-26, 1999; American Chemical Society: Washington, DC,
1999; MEDI-215.
(11) (a) Krueger, M.; Petrov, O.; Tierauch, K.; Siemeister, G. Prepa-
ration of 3,5-diamino-1,2,4-triazoles as inhibitors of cyclin de-
pendent kinases. PCT Int. Appl. WO 0294814, 2002. (b) Pierce,
A. C.; Arnost, M.; Davies, R. J.; Forster, C. J.; Galullo, V.; Grey,
R.; Ledeboer, M.; Tian, S.; Xu, J.; Binch, H.; Ledford, B.;
Messersmith, D.; Nanthakumar, S.; Jayara, A. Diaminotriazoles
useful as inhibitors of protein kinases. PCT Appl. WO 04046120,
2004.
(12) Lin, R.; Lu, Y.; Wetter, S. K.; Connolly, P. J.; Turchi, I. J.;
Murray, W. V.; Emanuel, S. L.; Gruninger, R. H.; Fuentes-
Pesquera, A. R.; Adams, M.; Pandey, N.; Moreno-Mazza, S.;
Middleton, S. A.; Jolliffe, L. K. 2,6-Diamino-3-acylpyridines as
cyclin-dependent kinase inhibitors: synthesis and biological
evaluation. Bioorg. Med. Chem. Lett. 2005, 15, 2221.
(13) Lin, R.; Connolly, P. J.; Wetter, S.; Huang, S.; Emanuel, S.;
Gruninger, R.; Middleton, S. Substituted triazole diamine
derivatives as kinase inhibitors. PCT Appl. WO 02057240, 2002.
(14) Presented in part: Emanuel, S. L.; Rugg, C.; Lin, R.; Connolly,
P. J.; Napier, C.; Hollister, B.; Hall, C.; Middleton, S. Evaluation
of the CDK inhibitor JNJ-7706621 (RWJ-387252) as a targeted
antitumor agent. Proceedings of the American Association for
Cancer Research, 95th Annual Meeting of the American As-
sociation for Cancer Research: Orlando, FL, March 27-31, 2004;
American Association for Cancer Research: Philadelphia, PA,
2004; Vol. 45, Abstract 833, p 191.
(15) Jenardanan, G. C.; Francis, M.; Deepa, S.; Rajaskekharan, K.
N. 1-(N-Arylthiocarbamoyl)amidino-3,5-dimethylpyrazoles-prepa-
ration and use in heterocycle synthesis. Synth. Commun. 1997,
27, 3457.
(16) Webb, R. L.; Eggleston, D. S.; Labaw, C. S.; Lewis, J. J.; Wert,
K. Diphenyl cyanocarbonimidate and dichlorodiphenoxymethane
as synthons for the construction of heterocyclic systems of
medicinal interest. J. Heterocycl. Chem. 1987, 24, 275.
tively, with only one treatment-related death in the 100
mg/kg group. These values represent survival gains of
approximately 3 weeks compared to vehicle alone (MDS
of 28.6 days), a significant survival extension vs vehicle-
treated animals, and demonstrate a good dose response
with treatment.
In summary, we have discovered a series of novel
1-acyl-1H-[1,2,4]triazole-3,5-diamine analogues that are
potent, selective, and presumably ATP-competitive CDK
inhibitors. Representative compounds inhibited the in
vitro growth of various human cancer cells including
melanoma, colon, prostate, ovarian, and breast cancer
cells. Compound 3b (JNJ-7706621) demonstrated sig-
nificant in vivo efficacy in the A375 human melanoma
tumor xenograft model in nude mice. The in vivo efficacy
could be attributed to inhibition of CDK1, but inhibi-
tions of other kinases such as FGF-R and VEGF-R2 may
also be partly responsible. A more detailed biological
evaluation of this and related compounds will be re-
ported in due course.
Acknowledgment. R.L. thanks Robert Ma and
Shawn Branum from the High OutPut Synthesis Team
for providing synthetic intermediates and thanks David
Palmer and Tong Xiao for helpful discussions.
Supporting Information Available: Experimental de-
tails of compounds reported, CDKs and kinase selectivity
assays, in vitro cell proliferation, X-ray crystallographic
ORTEP diagram of 3g, and HRMS, HPLC, and CHN analyses
of the compounds. This material is available free of charge via
for compound 3g have been deposited with the Cambridge
Crystallographic Data Centre as Supplementary Publication
No. CCDC270148 and can be obtained free of charge.
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