2306 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 7
Brief Articles
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type I receptor kinase activity: SB-431542. Mol. Pharmacol. 2002,
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L. M.; Reith, A. D.; Laping, N. J.; Hill, C. S. SB-431542 is a potent
and specific inhibitor of transforming growth factor-ꢀ superfamily type
I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and
ALK7. Mol. Pharmacol. 2002, 62 (1), 65–74.
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M. L.; Herron, D. K.; Lampe, J. W.; McCowan, J. R.; McMillen,
W. T.; Mort, N.; Parsons, S.; Smith, E. C. R.; Vieth, M.; Weir, L. C.;
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growth factor-ꢀ type 1 receptor kinase domain. J. Med. Chem. 2003,
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Figure 3. Effect of 15d (LY2109761) on the growth of the MX1
human breast cancer cell line in nude mice. Cells were implanted into
a group of 10 Charles River nude mice at 106 cells subcutaneously.
Compound 15d was administrated by BID oral gavage starting on day
7 (<100 cm3) and continued for 20 days. Tumors were allowed to
grow until a size of 2500 cm3 prior to study termination. Tumor volume
data were transformed to a log scale for analysis to equalize variance
across time and treatment groups. SAS PROC MIXED was used
separately for each treatment group with AR (1) autocorrelation to
calculate and plot adjusted means and standard errors at each time point.
Tumor growth delay was calculated as the difference in time to reach
1000 cm3 between treated and control groups.
organic layer was dried over Na2SO4 to give a pure white foam
without further purification (425 mg). LRMS (ES+) m/z 451.1 (M
+ 1)+.
A solution of mesylate (87 mg, 0.19 mmol) in morpholine (1
mL) was stirred at 50 °C for 4 h. After morpholine was removed
in vacuo, the crude product was dissolved in i-PrOH/CHCl3 (1:3)
and washed with sodium chloride. The organic layer was dried over
Na2SO4 and concentrated in vacuo to give a pure slight yellow solid
(15d, 83 mg, 81% overall yield for four steps). LRMS (ES+) m/z
442.0 (M + 1)+. HRMS (AP+) calcd for C26H27N5O2, 441.2165;
found, 441.2158. HPLC (system C), >99% (tR ) 0.45 min); (system
D), 97% (tR ) 2.37 min).
(17) Sawyer, J. S.; Anderson, B. D.; Beight, D. W.; Goodson, T.; Herron,
D. K.; Li, H.-Y.; McMillen, W. T.; Mort, N.; Parsons, S.; Smith,
E. C. R.; Britt, K. S.; Yan, L.; Zhang, F.; Yingling, J. M. Synthesis
and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-
pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-ꢀ
type I receptor kinase domain. Bioorg. Med. Chem. Lett. 2004, 14,
3581–3585.
(18) Li, H.-Y.; Wang, Y.; Yan, L.; Campbell, R. M.; Anderson, B. D.;
Wagner, J. R.; Yingling, J. M. Novel and potent transforming growth
factor beta type I receptor kinase domain inhibitor: 7-Amino 4-(2-yl-
5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline. Bioorg. Med.
Chem. Lett. 2004, 14, 3585–3588.
(19) Singh, J.; Ling, L. E.; Sawyer, J. S.; Lee, W. C.; Zhang, F.; Yingling,
J. M. Transforming the TGFꢀ pathway: Convergence of distinct lead
generation strategies on a novel kinase pharmacophore for TꢀR1
(ALK5). Curr. Opin. Drug DiscoVery DeV. 2004, 7, 437–445.
(20) Gellibert, F.; Woolven, J.; Fouchet, M.-H.; Mathews, N.; Goodland,
H.; Lovegrove, V.; Laroze, A.; Nguyen, V.-L.; Sautet, S.; Wang, R.;
Janson, C.; Smith, W.; Krysa, G.; Boullay, V.; de Gouville, A.-C.;
Huet, H.; Hartley, D. Identification of 1,5-naphthyridine derivatives
as a novel series of potent and selective TGF-ꢀ type I receptor
inhibitors. J. Med. Chem. 2004, 47, 4494–4506.
(21) Li, H.-Y.; Wang, Y.; Heap, C. R.; King, C.-H. R.; Mundla, S. R.;
Voss, M.; Clawson, D. K.; Yan, L.; Campbell, R. M.; Anderson, B. D.;
Wagner, J. R.; Britt, K.; Lu, K. X.; McMillen, W. T.; Yingling, J. M.
Dihydropyrrolopyrazole transforming growth factor-ꢀ type I receptor
kinase domain inhibitors: A novel benzimidazole series with selectivity
versus transforming growth factor-ꢀ type II receptor kinase and mixed
lineage kinase-7. J. Med. Chem. 2006, 49, 2138–2143.
(22) Kim, D.-K.; Jang, Y.; Lee, H. S.; Park, H.-J.; Yoo, J. Synthesis and
biological evaluation of 4(5)-(6-alkylpyridin-2-yl)imidazoles as trans-
forming growth factor-ꢀ type I receptor kinase inhibitors. J. Med.
Chem. 2007, 50, 3143–3147.
(23) Li, H.-Y.; Wang, Y.; McMillen, W. T.; Chatterjee, A.; Toth, J. E.;
Mundla, S. R.; Voss, M.; Boyer, R. D.; Sawyer, J. S. A concise
synthesis of quinazolinone TGF-ꢀ R1 inhibitor through one-pot three-
component Suzuki-Miyaura/etherification and imidata-amide rear-
rangement reactions. Tetrahedron 2007, 63, 11763–11770.
(24) Sawyer, J. S.; Schmitting, E. A.; Palkowitz, J. A.; Smith, W. J., III.
Synthesis of diaryl ethers, diaryl thioethers, and diaryl amines mediated
by potassium fluoride-alumina and 18-crown-6: Expansion of scope
and utility. J. Org. Chem. 1998, 63, 6338–6343.
Acknowledgment. We are grateful to Dr. Philip W. Iversen
and Mr. Jason R. Manro for their statistical contributions and
suggestions.
Supporting Information Available: General experimental
procedure and procedures for preparation of 7c–7f, 8–13, 14a, 15,
15a–c, 16a, 17a, 18–19, 20a,b, 21–23, and their precursors; NMR
data of 13a and 15d. Scheme for synthesis of 7a–f; Enzymatic and
cell-based assay procedures; IVTI PK and PD data for key
compounds; Kinase selectivity (15d); Table for screening of
alkylation condition of phenol 13; ADME surrogate data for key
compounds; HPLC purities of all target compounds, and HPLC
tracings of 15d. This material is available free of charge via the
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