Page 7 of 8
Journal of Medicinal Chemistry
with the severity of insulin resistance. Diabetes 2009, 58, 337ꢀ
acetate. Wash the organic phase with brine, dry over
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5
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343.
5.
MgSO4, filter, and concentrate to dryness. Purify the resiꢀ
due by silica gel chromatography, eluting with 10:40:50
acetonitrile/hexanes/dichloromethane to provide the title
compound (1.29 mmol, 550.00 mg, 45.46%). ESI (m/z)
426.2 (M+H).
Holland, W. L.; Brozinick, J. T.; Wang, L. P.; Hawkins,
E. D.; Sargent, K. M.; Liu, Y.; Narra, K.; Hoehn, K. L.; Knotts,
T. A.; Siesky, A.; Nelson, D. H.; Karathanasis, S. K.; Fontenot, G.
K.; Bimbaum, M. J.; Summers, S. A. Inhibition of ceramide synꢀ
thesis ameliorates glucocorticoidꢀ, saturatedꢀfatꢀ, and obesityꢀ
induced insulin resistance Cell Metab. 2007, 5, 167ꢀ179.
2-(4-(5-Heptanoyl-1-methyl-4,5,6,7-tetrahydro-
7
8
9
1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)-2-methylpropanoic
acid (2). Add 18 (1.29 mmoles; 547.00 mg), THF (31.59
mmoles; 2.57 mL), methanol (63.52 mmoles; 2.57 mL),
and NaOH (12.85 mmoles; 2.57 mL) to a round bottom
flask sequentially. Stir 8 hours, adjust the pH to 4ꢀ5 with
5.0N HCl and extract with ethyl acetate. Combine organic
phases, wash with brine and dry over MgSO4. Filter, and
concentrate to dryness to provide the title compound
(814.01 µmoles; 335.00 mg; 63.33% yield). ESI (m/z) 412
(M+1), LCMS Retention time 1.164min area 100.0%, 1H
NMR (400 MHz, DMSOꢀd6) δ 0.80ꢀ0.87 (m, 3 H), 1.17ꢀ
1.27 (m, 6 H), 1.44ꢀ1.53 (m, 8 H), 2.36ꢀ2.43 (m, 2 H),
2.65ꢀ2.79 (m, 2 H), 3.72ꢀ3.79 (m, 5 H), 4.65 (s, 2 H), 7.41
(d, J = 8.4 Hz, 2 H), 7.55ꢀ7.61 (m, 2 H), 12.34 (br s, 1 H).
6.
Jeong, T. S.; Schissel, S. L.; Tabas, I.; Pownall, H. J.;
Tall, A. R.; Jiang, X. Increased sphingomyelin content of plasma
lipoproteins in apolipoprotein E knockout mice reflects combined
production and catabolic defects and enhances reactivity with
mammalian sphingoꢀmyelinase. J. Clin. Invest. 1998, 101, 905ꢀ
912.
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Jiang, X. C.; Paultre, F.; Pearson, T. A.; Reed, R. G.;
Francis, C. K.; Lin, M.; Berglund, L.; Tall, A. R. Plasma sphinꢀ
gomyelin level as a risk factor for coronary artery disease. Arteri-
oscler. Thromb. Vasc. Biol. 2000, 20, 2614ꢀ26188.
8.
Park, T. ꢀS. P.; Panek, R. L. P.; Mueller, S. B.; Hanselꢀ
man, J. C.; Rosebury, W. S.; Robertson, A. W.; Kindt, E. K.;
Homan, R.; Karathanasis, S. K.; Rekhter, M. D. Inhibition of
sphingomyelin synthesis reduces atherogenesis in apolipoprotein
Eꢀknockout mice. Circulation 2004, 110, 3465ꢀ3471
9.
of insulin resistance. Cell Metab. 2012, 15, 585ꢀ594.
10. Li, Z., Park, T.ꢀS.; Li, Y.; Pan, X.; Iqbal, J.; Lu, D,;
Tang, W.; Yu, L.; Goldberg, I. J.; Hussain, M. M.; Jiang, X.ꢀC.
Serine palmitoyltransferase (SPT) deficient mice absorb less choꢀ
lesterol. Biochim. Biophys. Acta 2009, 1791, 297ꢀ306.
Chavez, J. A.; Summers, S. A. A ceramideꢀcentric view
ASSOCIATED CONTENT
Supporting Information. Experimental general procedures, in
vitro and in vivo pharmacology procedures and general methods.
This material is available free of charge via the Internet at
11.
Hojjati, M. R.; Li, Z.; Zhou, H.; Tang, S.; Huan, C.;
Ooi, E.; Lu, S.; Jiang, X. C. Effect of myriocin on plasma sphinꢀ
golipid metabolism and atherosclerosis in apoEꢀdeficient mice. J.
Biol. Chem. 2005, 280, 10284ꢀ10289.
AUTHOR INFORMATION
Corresponding Author
12.
Li, Z.; Li, Y.; Chakraborty, M.; Fan, Y.; Bui, H. H.,
Peake, D. A.; Kuo, MꢀS.; Xiao, X.; Cao, G.; Jianget, XꢀC. Liverꢀ
specific deficiency of serine palmitoyltransferase subunit 2 deꢀ
creases plasma sphingomyelin and increases apolipoprotein E
levels. J. Biol. Chem. 2009, 284, 27010ꢀ27019.
Author Contributions
The manuscript was written by M.J.G. and edited by J.B., M.M.,
I.C.G.V. and L.A.A. All authors have given approval to the final
version of the manuscript.
13.
Chiba, K., Maeda, Y., Seki, N., Kataoka, H., Sugahara,
K. Role of sphingosine 1ꢀphosphate (S1P) and effects of finꢀ
golimod, an S1P receptor 1 functional antagonist in lymphocyte
circulation and autoimmune diseases. AIMS Molecular Science,
2014, 1, 162ꢀ182.
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
14.
Fujita T., Inoue K., Yamamoto S., Ikumoto, T., Sasaki,
SPT; serine palmitoyl transferase, T2DM; type 2 diabetes, DIO;
diet induced obese, OGTT; oral glucose tolerance test, LDL; low
density liproprotein, HDL; high density liproprotein, THF; tetraꢀ
hydrofuran, DMF; dimethylformamide, TFA; trifluoroacetic acid
S., Toyama, R., Chiba, K., Hoshino, Y., Okumoto, T. Fungal meꢀ
tabolites. Part 11. A potent immunosuppressive activity found in
Isaria sinclairii metabolite. J Antibiot. 1994, 47, 208ꢀ215.
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