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

doi:10.6023/cjoc201511037

Chin. J. Org. Chem. ›› 2016, Vol. 36 ›› Issue (6): 1359-1367.DOI: 10.6023/cjoc201511037 Previous Articles Next Articles

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基于天然产物Aphadilactone C结构关键片段的二酰基甘油酰基转移酶1抑制剂的设计与合成

李丹^a, 尹建朋^b, 李静雅^b, 南发俊^b

a 华东师范大学化学与分子工程学院上海 200062;
b 中国科学院上海药物研究所国家新药筛选中心上海 201203

收稿日期:2015-11-18 修回日期:2016-01-12 发布日期:2016-02-18
通讯作者: 南发俊 E-mail:fjnan@simm.ac.cn
基金资助:
上海市重性精神病重点实验室开放课题(No.13DZ226050014K-10)资助项目.

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

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

aCollege 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

Received:2015-11-18 Revised:2016-01-12 Published:2016-02-18
Supported by:
Project supported by the Shanghai Key Laboratory of Psychotic Disorders (No. 13DZ226050014K-10).

1. Design and Synthesis of Diacylglycerol Acyltransferase 1 Inhibitors Based on Aphadilactone C.PDF(9315KB)

Abstract

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.

Key words: aphadilactone C, DGAT1, selective inhibitor, PF-04620110, AZD-7687

Cite this article

Li Dan, Yin Jianpeng, Li Jingya, Nan Fajun. Design and Synthesis of Diacylglycerol Acyltransferase 1 Inhibitors Based on Aphadilactone C[J]. Chin. J. Org. Chem., 2016, 36(6): 1359-1367.

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[1] Mu, H.; Høy, C. E. Prog. Lipid Res. 2004, 43, 105.
[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] Lardizabal, K. D.; Mai, J. T.; Wagner, N. W.; Wyrick, A.; Voelker, T.; Hawkins, D. J. J. Biol. Chem. 2001, 276, 38862.
[4] (a) 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] (a) 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] 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] 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] Yin, J. P.; Gu, M.; Li, Y.; Nan, F. J. J. Org. Chem. 2014, 79, 6294.
[9] (a) 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] 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] 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] Mordant, C.; Dunkelmann, P.; Ratovelomanana-Vidal, V.; Genet, J.-P. Eur. J. Org. Chem. 2004, 14, 3017.
[13] Efthymiou, T. C.; Huynh, V.; Oentoro, J., Peel, B., Desaulniers, J. P. Bioorg. Med. Chem. Lett. 2012, 22, 1722.
[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] Coleman, R. A. Methods Enzymol. 1992, 209, 98.

基于天然产物Aphadilactone C结构关键片段的二酰基甘油酰基转移酶1抑制剂的设计与合成

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

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