5900 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19
Letters
(12) Haluska, P.; Carboni, J. M.; Loegering, D. A.; Lee, F. Y.; Wittman,
M.; Saulnier, M. G.; Frennesson, D. B.; Kalli, D. A.; Conover, C. A.;
Attar, R. M.; Kaufmann, S. H.; Gottardis, M.; Erlichman, C. In vitro
and in vivo antitumor effects of dual insulin-like growth factor-1/
insulin receptor inhibitor, BMS-554417. Cancer Res. 2006, 66, 362–
371.
(13) Velaparthi, U.; Liu, P.; Balasubramanian, B.; Carboni, J.; Attar, R.;
Gottardis, M.; Li, A.; Greer, A.; Zoeckler, M.; Wittman, M. D.; Vyas,
D. Imidazole moiety replacements in the 3-(1H-benzo[d]imidazole-
2-yl)pyridine-2(1H)-one inhibitors of insulin-like growth factor recep-
tor-1 (IGF-1R) to improve cytochrome P450 profile. Bioorg. Med.
Chem. Lett. 2007, 17, 3072–3076.
(14) Velaparthi, U.; Wittman, M.; Liu, P.; Stoffan, K.; Zimmermann, K.;
Sang, X.; Carboni, J.; Li, A.; Attar, R.; Gottardis, M.; Greer, A.; Chang,
C. Y.; Jacobsen, B. L.; Sack, J. S.; Sun, Y.; Langley, D. R.;
Balasubramanian, B.; Vyas, D. Discovery and initial SAR of 3-(1H-
benzo[d]imidazole-2-yl)pyridine-2(1H)-ones as inhibitors of insulin-
like growth factor-1 recpetor (IGF-1R). Bioorg. Med. Chem. Lett. 2007,
17, 2317–2321.
(15) Wittman, M. D.; Balasubramanian, B.; Stoffan, K.; Velaparthi, U.;
Liu, P.; Krishnanathan, S.; Carboni, J.; Li, A.; Greer, A.; Attar, R.;
Gottardis, M.; Chang, C.; Jacobson, B.; Sun, Y.; Hansel, S.; Zoeckler,
M.; Vyas, D. Novel 1H-(benzoimidazole-2-yl)-1H-pyridine-2-one
inhibitors of insulin-like growth factor I (IGF-1R) kinase. Bioorg. Med.
Chem. Lett. 2007, 17, 974–977.
piperidines with potent IGF-1R inhibition. The work led to the
identification of 10, a compound with reduced CYP3A4
inhibition and PXR transactivation and thereby lowered the risk
for potential for drug-drug interactions. Compound 10 was also
shown to have improved aqueous solubility, reduced plasma
protein binding, and efficacy on oral administration in multiple
xenograft in vivo models.
Acknowledgment. The authors thank the Lead Profiling and
analytical departments of Bristol-Myers Squibb Company,
Wallingford, CT, for generating the CYP inhibition, PXR
transactivation, and analytical data.
Note Added after ASAP Publication. This manuscript was
released ASAP on September 3, 2008 with typographical errors in
Table 5. The correct version was released on September 5, 2008.
Supporting Information Available: Experimental details and
analytical data for compound 10 are included. This material is
(16) Mulvihill, M. J.; Ji, Q.-S.; Werner, D.; Beck, P.; Cesario, C.; Cooke,
A.; Cox, M.; Crew, A.; Dong, H.; Feng, L.; Foreman, K. W.; Mak,
G.; Nigro, A.; O’Connor, M.; Saroglou, L.; Stolz, K. M.; Sujka, I.;
Volk, B.; Weng, Q.; Wilkes, R. 1,3-Disubstitued imidazol[1,5-
a]pyrazines as insulin-like growth factor-I receptor (IGF-IR) inhibitors.
Bioorg. Med. Chem. Lett. 2007, 17 (4), 1091–1097.
(17) Hubbard, R. D.; Bamaung, N. Y.; Palazzo, F.; Zhang, Q.; Kovar, P.;
Osterling, D. J.; Hu, X.; Wilsbacher, J. L.; Johnson, E. F.; Bouska, J.;
Wang, J.; Bell, R. L.; Davidsen, S. K.; Sheppard, G. S. Pyrazolo[3,4-
d]pyridimidines as potent inhibitors of the insulin-like growth factor
receptor (IGF-IR). Bioorg. Med. Chem. Lett. 2007, 17, 5406–5409.
(18) Recently OSI Pharmaceuticals and Exlexis have reported that their
IGF-1R inhibitors, OSI-906 and XL-228, respectively, entered phase
I clinical trials.
(19) (a) Moore, J. T.; Kliewer, S. A. Use of the nuclear receptor PXR to
preedict drug interactions. Toxicology 2003, 153, 1–10. (b) Gao, Y. D.;
Olson, S. H.; Balkovec, J. M.; Zhu, Y.; Royo, I.; Yabut, J.; Evers, R.;
Tan, E. Y.; Tang, W.; Hartley, D. P.; Mosley, R. T. Attenuating
pregnane X receptor (PXR) activation: A molecular modelling
approach. Xenobiotica 2007, 37 (2), 124–138.
(20) Carboni, J. M.; Lee, A. V.; Hadsell, D. L.; Rowley, B. R.; Lee, F. Y.;
Bol, D. K.; Camuso, A. E.; Gottardis, M.; Greer, A. F.; Ho, C. P.;
Hurlburt, W.; Li, A.; Saulnier, M. G.; Velaparthi, U.; Wang, C.; Wen,
M.-L.; Westhouse, R. A.; Wittman, M.; Zimmermann, K.; Rupnow,
B. A.; Wong, T. W. Tumor development by transgenic expression of
a constitutively active insulin-like growth factor-1 receptor. Cancer
Res. 2005, 65, 3781–3787.
(21) Wittman, D. M. B. Balasubramanian, N.; Velaparthi, U.; Zimmermann,
K.; Saulnier, G. M.; Liu, P.; Sang, X.; Frennesson, B. D.; Stoffan,
K. M.; Tarrant, J.; Marinier, A.; Roy, S. Preparation of 2-(4-substituted-
2-oxo-1,2-dihydropyridine-3-yl)-benzimidazoles as novel tyrosine ki-
nase inhibitors. U.S. Patent US2004/044203 A1, 2004.
(22) Saulnier, M. G.; Frennessn, D. B.; Wittman, M. D.; Zimmermann,
K.; Velaparthi, U.; Langley, D. R.; Struzynski, C.; Sang, X.; Carboni,
J.; Li, A.; Greer, A.; Yang, Z.; Balimane, P.; Gottardis, M.; Attar, M.;
Vyas, D. 2-(1H-Imidazol-4-yl)ethanamine and 2-(1H-pyrazol-1-yl) etha-
namine side chain variants of the IGF-1R inhibitor BMS-536924.
Bioorg. Med. Chem. Lett. 2008, 18, 1702–1707.
(23) The potential disruption of glucose homeostasis by compound 10
arising from the inhibition of IR was evaluated in vivo in oral glucose
tolerance test (OGTT). The test was performed in mice at both 50
and 100 mpk and found that significant glucose elevation was not
observed prior to glucose challenge. However, after glucose challenge,
an elevation of glucose level is observed at the 100 mpk dose that is
very similar to the effect observed for compound 1 as reported in
reference 10.
References
(1) Hubbard, S. R.; Miller, W. T. Receptor tyrosine kinases: mechanisms
of activation and signaling. Curr. Opin. Cell Biol. 2007, 19, 117–
123.
(2) Liao, J, J. Molecular Recognition of Protein Kinase Binding Pockets
for Design of Potent and Selective Kinase Inhibitors. J. Med. Chem.
2007, 50, 409–424.
(3) LeRoith, D.; Roberts, C. T. The insulin-like growth factor system and
cancer. Cancer Lett. 2003, 195, 127–137.
(4) Baserga, R.; Peruzzi, F.; Reiss, K. The IGF-1 receptor in cancer
biology. Int. J. Cancer 2003, 107, 873–877.
(5) Yu, H.; Rohan, T. J. Role of insulin-like growth factor family in cancer
development and progression. Natl. Cancer Inst. 2000, 92 (18), 1472–
1489.
(6) White, P. J.; Fogarty, R. D.; Werther, G. A.; Wraight, C. J. Antisense
inhibition of IGF-1 receptor expression in HaCaT keratinocytes: a
model for antisense strategies in keratinocytes. Antisense. Nucleic Acid
Drug DeV. 2000, 10, 195–203.
(7) De Leon, D. D.; Wilson, D. M.; Powers, M.; Rosenfield, R. G. Effects
of insulin-like growth factors (IGFs) and IGF receptor antibodies on
the proliferation of human breast cancer cells. Growth Factors 1992,
6, 327–336.
(8) Reiss, K.; D’Ambosio, C.; Tu, X.; Tu, C.; Baserga, R. Inhibition of
tumor growth by a dominant negative mutant of the insulin-like growth
factor I receptor with a bystander effect. Clin. Cancer Res. 1998, 4,
2647–2655.
(9) Chan, J. M.; Stampfer, M. J.; Giovannucci, E.; Gann, P. H.; Ma, J.;
Wilkinson, P.; Hennekesn, C. H.; Pollak, M. Plasma insulin-like growth
factor-I and prostate cancer risk: a prospective study. Science
(Washington, D.C.) 1998, 279, 563–566.
(10) Wittman, M.; Carboni, J.; Attar, F.; Balasubramanian, B.; Balimane,
P.; Brassil, P.; Beaulieu, F.; Chang, C.; Clarke, W.; Dell, J.; Eummer,
J.; Frennesson, D.; Gottardis, M.; Greer, A.; Hansel, S.; Hurlburt, W.;
Jacobson, B.; Krishnananthan, S.; Lee, F. Y.; Li, A.; Lin, T.-A.; Liu,
P.; Ouellet, C.; Sang, X.; Saulnier, M. G.; Stoffan, K.; Sun, Y.;
Velaparthi, U.; Vyas, D.; Wong, H.; Yang, Z.; Zimmermann, K.;
Zoeckler, M.; Vyas, D. Discovery of a (1H-benzimidazol-2-yl)-1H-
pyridine-2-one (BMS-536924) inhibitor of insulin-like growth factor
I receptor kinase with in vivo antitumor activity. J. Med. Chem. 2005,
48, 5639–5643and references cited therein.
(11) Ji, Q.-S.; Mulvihill, M.; Rosenfeld-Franklin, M.; Cooke, A.; Feng,
L.; Mak, G.; O’Connor, M.; Yao, Y.; Pirritt, C.; Buck, E.; Eyzaguirre,
A.; Arnold, L. D.; Gibson, N. W.; Pachter, J. A. A novel, potent, and
selective insulin-like growth factor-1 receptor kinase inhibitor blocks
insulin-like growth factor-1 receptor signaling in vitro and inhibits
insulin-like growth factor-1 receptor dependent tumor growth in vivo.
Mol. Cancer. Ther. 2007, 6 (8), 2158–2167.
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