Substituted Benzamides Containing Azaspiro Rings as Upregulators of Apolipoprotein A-I Transcription
Abstract
:1. Introduction
2. Results and Discussion
2.1. Screening for Compounds Upregulating Apo A-I transcription
2.2. Biological Activity of Substituted Benzamide Containing Aza Spiro Ring Analogs
Compound entry | R' | R | Activity (fold induction) | ||
---|---|---|---|---|---|
In series | In library | 5 μg/mL | 10 μg/mL | ||
A-1 | 4011061 | 3-CF3 | 1.22 | 1.01 | |
A-2 | 4011071 | 3-CF3,4-Cl | 3.59 | 3.08 | |
A-3 | 4011091 | 4-N(CH3)2 | 1.33 | 1.03 | |
A-4 | 4021671 | 3-CF3,4-Cl | 1.00 | 0.99 | |
B-1 | 4010301 | 3-CF3,4-F | 2.97 | 3.08 | |
B-2 | 4010271 | H | 1.16 | 1.10 | |
B-3 | 4010281 | 3-OCH3 | 1.20 | 1.08 | |
B-4 | 4011531 | 3-CF3 | 1.41 | 1.65 | |
B-5 | 4011561 | 3-CF3,4-F | 2.85 | 2.66 | |
B-6 | 4011551 | 3-CF3,4-CH3 | 1.18 | 1.01 | |
B-7 | 4011521 | 3-OCH3 | 1.18 | 1.02 | |
B-8 | 4011571 | 3-N(CH3)2 | 1.06 | 1.00 | |
C-1 | 4010021 | 2-CF3 | 1.49 | 1.79 | |
C-2 | 4010031 | 3-CF3 | 1.96 | 1.81 | |
C-3 | 4010041 | 3-N(CH3)2 | 1.17 | 1.00 | |
C-4 | 4011151 | 2-CF3 | 1.18 | 0.94 | |
C-5 | 4011161 | 3-CF3 | 1.31 | 1.30 | |
D-1 | 4010731 | 3-CF3,4-Cl | 2.37 | 2.24 | |
D-2 | 4010751 | 3-CF3,4-CH3 | 2.87 | 2.74 | |
E-1 | 4010531 | 3-CF3 | 1.24 | 1.17 | |
E-2 | 4010571 | 3-CF3,4-Cl | 3.34 | 2.94 |
2.3. Structure-Activity Relationship Analysis
3. Experimental
3.1. General
3.2. Cell Culture
3.3. Compounds
3.4. Cell-Based Screening Assay
4. Conclusions
Acknowledgements
- Sample Availability: Samples of the compounds listed in Table 1 are commercially available.
References and notes
- Brewer, H.B. High-density lipoproteins: A new potential therapeutic target for the prevention of cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 2004, 24, 387–391. [Google Scholar] [CrossRef]
- Rader, D.J. Molecular regulation of HDL metabolism and function: Implications for novel therapies. J. Clin. Invest. 2006, 116, 3090–3100. [Google Scholar] [CrossRef]
- Boden, W.E. High-density lipoprotein cholesterol as an independent risk factor in cardiovascular disease: Assessing the data from Framingham to the veterans Affairs High-density lipoprotein intervention trial. Am. J. Cardiol. 2000, 86, 19L–22L. [Google Scholar] [CrossRef]
- Duffy, D.; Rader, D.J. Emerging therapies targeting high-density lipoprotein metabolism and reverse cholesterol transport. Circulation 2006, 113, 1140–1150. [Google Scholar] [CrossRef]
- Tall, A.R. Plasma high density lipoproteins: Metabolism and relationship to atherogenesis. J. Clin. Invest. 1990, 86, 379–384. [Google Scholar] [CrossRef]
- Shah, P.K. Evolving concepts on benefits and risks associated with therapeutic strategies to raise HDL. Curr. Opin. Cardiol. 2010, 25, 603–608. [Google Scholar] [CrossRef]
- Rubin, E.M.; Krauss, R.M.; Spangler, E.A.; Verstuyft, J.G.; Clift, S.M. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein A-I. Nature 1991, 353, 265–267. [Google Scholar]
- Tangirala, R.K.; Tsukamoto, K.; Chun, S.H.; Usher, D.; Puré, E.; Rader, D.J. Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice. Circulation 1999, 100, 1816–1822. [Google Scholar]
- de Goma, E.M.; Rader, D.J. Novel HDL-directed pharmacotherapeutic strategies. Nat. Rev. Cardiol. 2011, 8, 266–277. [Google Scholar] [CrossRef]
- Nicholls, S.J.; Gordon, A.; Johansson, J.; Wolski, K.; Ballantyne, C.M.; Kastelein, J.J.; Taylor, A.; Borgman, M.; Nissen, S.E. Efficacy and safety of a novel oral inducer of apolipoprotein A-I synthesis in statin-treated patients with stable coronary artery disease: A randomized controlled trial. J. Am. Coll. Cardiol. 2011, 57, 1111–1119. [Google Scholar]
- Du, Y.; Wang, L.; Wang, L.F.; Si, S.Y.; Yang, Y.; Hong, B. Establishment of a high-throughput screening model for identifying up-regulator of human Apo A-I expression. Chin. Med. Biotechnol. 2011, 6, 178–183. [Google Scholar]
- Vu-Dac, N.; Chopin-Delannoy, S.; Gervois, P.; Bonnelye, E.; Martin, G.; Fruchart, J.C.; Laudet, V.; Staels, B. The nuclear receptors peroxisome proliferator-activated receptor alpha and Rev-erbalpha mediate the species-specific regulation of apolipoprotein A-I expression by fibrates. J. Biol. Chem. 1998, 273, 25713–25720. [Google Scholar]
- Zhang, L.H.; Kamanna, V.S.; Ganji, S.H.; Xiong, X.M.; Kashyap, M.L. Pioglitazone increases apolipoprotein A-I production by directly enhancing PPRE-dependent transcription in HepG2 cells. J. Lipid. Res. 2010, 51, 2211–2222. [Google Scholar] [CrossRef]
- Zhang, X.K.; Lehmann, J.; Hoffmann, B.; Dawson, M.I.; Cameron, J.; Graupner, G.; Hermann, T.; Tran, P.; Pfahl, M. Homodimer formation of retinoid X receptor induced by 9-cis retinoic acid. Nature 1992, 358, 587–591. [Google Scholar] [CrossRef]
- Wong Norman, C.W. Use of resveratrol to regulate expression of apolipoprotein A1. United States Patent Application Publication 20040033480A1, 19 February 2004. [Google Scholar]
- McNeill, E. RVX-208, a stimulator of apolipoprotein AI gene expression for the treatment of cardiovascular diseases. Curr. Opin. Investig. Drugs 2010, 11, 357–364. [Google Scholar]
- Jiang, W.; Si, S.Y.; Chen, X.P.; Wang, L.; Zhuang, X.L.; Zou, J.; Chen, H.S.; Cao, L.X.; Feng, H.; Chen, L. Development and application of microbial natural products database. J. Chin. Antibiot. 2006, 36, 119–121. [Google Scholar]
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
Share and Cite
Du, Y.; Yang, Y.; Jiang, W.; Wang, L.; Jia, X.-J.; Si, S.-Y.; Chen, X.-F.; Hong, B. Substituted Benzamides Containing Azaspiro Rings as Upregulators of Apolipoprotein A-I Transcription. Molecules 2012, 17, 7379-7386. https://doi.org/10.3390/molecules17067379
Du Y, Yang Y, Jiang W, Wang L, Jia X-J, Si S-Y, Chen X-F, Hong B. Substituted Benzamides Containing Azaspiro Rings as Upregulators of Apolipoprotein A-I Transcription. Molecules. 2012; 17(6):7379-7386. https://doi.org/10.3390/molecules17067379
Chicago/Turabian StyleDu, Yu, Yuan Yang, Wei Jiang, Li Wang, Xiao-Jian Jia, Shu-Yi Si, Xiao-Fang Chen, and Bin Hong. 2012. "Substituted Benzamides Containing Azaspiro Rings as Upregulators of Apolipoprotein A-I Transcription" Molecules 17, no. 6: 7379-7386. https://doi.org/10.3390/molecules17067379