Citation: Li Dan, Yin Jianpeng, Li Jingya, Nan Fajun. Design and Synthesis of Diacylglycerol Acyltransferase 1 Inhibitors Based on Aphadilactone C[J]. Chinese Journal of Organic Chemistry, ;2016, 36(6): 1359-1367. doi: 10.6023/cjoc201511037 shu

Design and Synthesis of Diacylglycerol Acyltransferase 1 Inhibitors Based on Aphadilactone C

Li Dan ^a ,
Yin Jianpeng ^b ,
Li Jingya ^b ,
Nan Fajun ^b,*,,

a.
College of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062
b.
The National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203

Corresponding author: Nan Fajun, fjnan@simm.ac.cn
Received Date: 18 November 2015
Revised Date: 12 January 2016

Fund Project: Project supported by the Shanghai Key Laboratory of Psychotic Disorders No. 13DZ226050014K-10

Figures(6)

Diacylglycerol acyltransferase (DGAT), the only limited enzyme in the synthesis of triacylglycerol (TAG), is regarded as an important therapeutic target for human obesity and other metabolic syndromes. Compounds 5~8 were designed and synthesized, in which the lactone group of aphadilactone C was introduced into the PF-04620110 and AZD-7687, which have entered into the clinical research, to verify whether the lactone in aphadilactone C played the same role as carboxylic group in PF-04620110 and AZD-7687. The final vitro assay showed that compounds 5~8 have not the inhibition activity to DGAT1. This might suggest that inhibition mechanism of aphadilactone C was not the same as PF-04620110 and AZD-7687.
- aphadilactone C,
- DGAT1,
- selective inhibitor,
- PF-04620110,
- AZD-7687
1. [1]
  Mu, H.; Høy, C. E. Prog. Lipid Res. 2004, 43, 105.
2. [2]
  Cases, S.; Stone, S. J.; Zhou, P.; Yen, E.; Tow, B.; Lardizabal, K. D.; Voelker, T.; Farese, R. V. Jr. J. Biol. Chem. 2001, 276, 38870.
3. [3]
  Lardizabal, K. D.; Mai, J. T.; Wagner, N. W.; Wyrick, A.; Voelker, T.; Hawkins, D. J. J. Biol. Chem. 2001, 276, 38862.
4. [4]
  Smith, S. J.; Cases, S.; Jensen, D. R.; Chen, H. C.; Sande, E.; Tow, B.; Sanan, D. A.; Raber, J.; Eckel, R. H.; Farese, R. V. Jr. Nat. Genet. 2000, 25, 87. (b) Chen, H. C.; Smith, S. J.; Ladha, Z.; Jensen, D. R.; Ferreira, L. D.; Pulawa, L. K.; McGuire, J. G.; Pitas, R. E.; Eckel, R. H.; Farese, R. V. Jr. J. Clin. Invest. 2002, 109, 1049. (c) Chen, H. C.; Jensen, D. R.; Myers, H. M.; Eckel, R. H.; Farese, R. V. Jr. J. Clin. Invest. 2003, 111, 1715. (d) Chen, H. C.; Ladha, Z.; Smith, S. J.; Farese, R. V. Jr. Am. J. Physiol. Endocrinol. Metab. 2003, 284, 213.
5. [5]
  Stone, S. J.; Myers, H. M.; Watkins, S. M.; Brown, B. E.; Feingold, K. R.; Elias, P. M.; Farese, R. V. Jr. J. Biol. Chem. 2004, 279, 11767. (b) Chen, H. C.; Farese, R. V. Jr. Arterioscler., Thromb., Vasc. Biol. 2005, 25, 482.
6. [6]
  Dow, R. L.; Andrews, M. P.; Li, J. C.; Gibbs, E. M.; Guzman-Perez, A.; LaPerle, J. L.; Li, Q.; Mather, D.; Munchhof, M. J.; Niosi, M.; Patel, L.; Perreault, C.; Tapley, S.; Zavadosk, W. J. Bioorg. Med. Chem. 2013, 21, 5081.
7. [7]
  Liu, J.; He, X. F.; Wang, G. H.; Merino, E. F.; Yang, S. P.; Zhu, R. X.; Gan, L. S.; Zhang, H.; Cassera, M. B.; Wang, H. Y.; Kingston, D. G. I.; Yue, J. M. J. Org. Chem. 2013, 79, 599.
8. [8]
  Yin, J. P.; Gu, M.; Li, Y.; Nan, F. J. J. Org. Chem. 2014, 79, 6294.
9. [9]
  Devita, R. J.; Pinto, S. J. Med. Chem. 2013, 56, 9820. (b) Barlind, J. G.; Bauer, U. A.; Birch, A. M.; Birtles, S.; Buckett, L. K.; Butlin, R. J.; Davies, R. D. M.; Eriksson, J. W.; Hammond, C. D.; Hovland, R.; Johannesson, P.; Johansson, M. J.; Kemmitt, P. D.; Lindmark, B. T.; Gutierrez, P. M.; Noeske, T. A.; Nordin, A.; O'Donnell, C. J.; Petersson, A. U.; Redzic, A.; Turnbull, A. V.; Vinblad, J. J. Med. Chem. 2012, 55, 10610.
10. [10]
  Dow, R. L.; Andrews, M.; Aspnes, G. E.; Balan, G.; Gibbs, E. M.; Perez, A. G.; Karki, K.; LaPerle, J. L.; Li, J. C.; Litchfield, J.; Munchhof, M. J.; Perreault, C.; Patel, L. Bioorg. Med. Chem. Lett. 2011, 21, 6122.
11. [11]
  Zhou, G.; Ting, P. C.; Wishart, G.; Zorn, N.; Aslanian, R. G.; Lin, M.; Smith, M.; Walker, S. S.; Cook, J.; Heek, M. V.; Lachowicz, J. Bioorg. Med. Chem. Lett. 2014, 24, 1790.
12. [12]
  Mordant, C.; Dunkelmann, P.; Ratovelomanana-Vidal, V.; Genet, J.-P. Eur. J. Org. Chem. 2004, 14, 3017.
13. [13]
  Efthymiou, T. C.; Huynh, V.; Oentoro, J., Peel, B., Desaulniers, J. P. Bioorg. Med. Chem. Lett. 2012, 22, 1722.
14. [14]
  Wu, W. N.; Mckown, L. A. Optimization in Drug Discovery, Vol. 11, Eds.: Yan, Z.-Y.; Caldwell, G. W., Humana Press Inc., Totowa, 2004, p. 163.
15. [15]
  Coleman, R. A. Methods Enzymol. 1992, 209, 98.
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