PPAR激动剂的开发与应用

doi:10.5246/jcps.2018.04.023

中国药学(英文版) ›› 2018, Vol. 27 ›› Issue (4): 215-228.DOI: 10.5246/jcps.2018.04.023

• 【综述】 • 下一篇

PPAR激动剂的开发与应用

辛健, 徐向楠, 王玉平, 张振涛^*, 马宇衡^*

内蒙古医科大学药学院药物化学教研室, 内蒙古呼和浩特 010110

收稿日期:2017-12-07 修回日期:2017-12-10 出版日期:2018-04-30 发布日期:2018-04-03
通讯作者: Tel.: +86-471-6653149, E-mail: 857805364@qq.com, myhstar@126.com
作者简介:马宇衡博士, 2009年毕业于北京大学药学院, 获药物化学专业博士学位; 2009–2012年于北京大学工学院、化学院从事博士后研究; 2012年10月任内蒙古医科大学药学院药物化学专业副教授。研究方向: 抗肿瘤药物的研究与开发。
基金资助:
National Natural Science Foundation of China (Grant No. 21562033).

The development and application of peroxisome proliferator-activated receptor (PPAR) modulator

Jian Xin, Xiangnan Xu, Yuping Wang, Zhentao Zhang^*, Yuheng Ma^*

School of Pharmacy, Inner Mongolia Medical University, Hohhot 010110, China

Received:2017-12-07 Revised:2017-12-10 Online:2018-04-30 Published:2018-04-03
Contact: Tel.: +86-471-6653149, E-mail: 857805364@qq.com, myhstar@126.com
About author:In 2009, Dr. Ma obtained his Ph.D. degree in medicinal chemistry from School of Pharmaceutical Sciences, Peking University. During 2009–2012, he did postdoctoral research at college of engineering and college of chemistry and molecular engineering, Peking University. In October 2012, he joined the School of Pharmacy at Inner Mongolia Medicinal University as an Associate Professor. His research interest is discovery de novo antitumor drug.
Supported by:
National Natural Science Foundation of China (Grant No. 21562033).

摘要/Abstract

摘要：

过氧化物酶体增殖物激活受体(PPARs), 包括 PPARα, PPARβ/δ 和PPARγ三种亚型, 属于核受体家族成员并且在糖代谢和脂代谢的过程中扮演了重要的角色。基于PPAR激动剂在代谢综合征以及二型糖尿病治疗中的巨大优势, PPAR激动剂被给予了极大的关注, 然而严重的临床不良反应极大地制约了PPAR激动剂的开发与应用。因此在新一代PPAR激动剂的研发中, 选择性与安全性将被纳入研究与开发的重要环节。近年来一系列PPAR双或泛激动剂基于临床需求应运而生, 进一步研究表明部分激动剂具有减少副作用并达到良好治疗效果的优势。本文综述了PPAR受体的结构特征, 阐述了PPAR激动剂在药物分子设计环节上的一些思路, 列举并分析了近年来开发的一系列PPAR双或泛激动剂。

关键词: PPAR受体, 双激动剂, 代谢综合征, 二型糖尿病

Abstract:

The peroxisome proliferator-activated receptors (PPARs), PPARα, PPARβ/δ and PPARγ, are ligand-activated transcriptional factors, which belong to the nuclear receptor super family and play crucial roles in glucose and lipid metabolism. Based on the impressive advantages of PPAR agonists (like TZD and fibrate compounds) in the treatment of metabolic syndrome and type 2 diebetes, PPAR modulators have doubtlessly grabbed much more attention. However, serious clinical adverse effects, especially for PPARγ agonists, hinder the development of PPAR agonist. Therefore, the selectivity and safety would be the key points and have been taken into the consideration for novel generation PPAR agonist research, and then several dual- or pan-PPAR modulators have emerged. Furthermore, experimental study indicates that partial agonists can neutralize the side effect and achieve modest therapeutic effect. This review summaries structural features of PPAR receptors, illustrates the method of PPAR modulator design, then lists and analyzes recent dual- and pan- agonists.

Key words: PPAR receptors, Dual- modulator, Metabolic syndrome, T2D

中图分类号:

R916

Supporting:

辛健, 徐向楠, 王玉平, 张振涛, 马宇衡. PPAR激动剂的开发与应用[J]. 中国药学(英文版), 2018, 27(4): 215-228.

Jian Xin, Xiangnan Xu, Yuping Wang, Zhentao Zhang, Yuheng Ma. The development and application of peroxisome proliferator-activated receptor (PPAR) modulator[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(4): 215-228.

参考文献

[1] Global Status Report on Noncommunicable disease. 2014. World Health Organization.

[2] Emily, J.G.; Derek, L.R.; Rebeca, F.; Irini, M.A.; Anupma, N.; Jennifer, L.T.; Nina, A.B. Metabolic syndrome and pre-diabetes contribute to racial disparities in breast cancer outcomes: hypothesis and proposed pathways. Diabetes Metab. Res. Rev. 2016, 32, 745-753.

[3] Scott, M.G. Pre-Diabetes, Metabolic Syndrome, and Cardiovasular Risk. J. Am. Coll. Cardiol. 2012, 59, 635-643.

[4] David, B.S. PPARγ as a metabolic regulator: insights from genomics and pharmacology. Expert Rev. Mol. Med. 2005, 7, 1-16.

[5] Shigeki, S.; Kyoko, O.; Koichi, K.; Shigeki, I.; Maki, I.; Takehiro, S.; Yoshiaki, K.; Yasushi, K.; Koji, M. Design, Synthesis, and Structure-Activity Relationship Studies of Novel 2,4,6,-Trisubstituted-5-pyrimidinecarboxylic Acids as Peroxisome Proliferator-Activated Receptor γ (PPARγ) Partial Agonists with Comparable Antidiabetic Efficacy to Rosiglitazone. J. Med. Chem. 2010, 53, 5012-5024.

[6] Brad, R.H. Peroxisome Proiferator-Activated Receptor α/γ Dual Agonists for the Treatment of Type 2 Diabetes. J. Med. Chem. 2004, 47, 4118-4127.

[7] Ouliana, Z.; Stephane, P.; Niko, M.; Daniel, B.; Jorge, P. Peroxisome Proliferator-activated Recptors. Curr. Atheroscler. Rep. 2002, 4, 59-64.

[8] Limei, W.; Birgit, W.; Eva-Maria, P.W.; Martina, B.; Xin, L.; Clemens, M.; Tina, B.; Stefan, S.; Judith, M.R.; Elke, H.H.; Daniela, S.; Brigitte, K.; Rudolf, B.; Hermann, S.; Verena, M.D.; Atanas, G.A. Natural product agonists of peroxisome proliferator-activated receptor gama (PPARγ): a review. Biochem. Pharmacol. 2014, 92, 73-89.

[9] Shirin, K.; Ariela, L.; Arie, G.; Hanoch, S.; Shlomo, S. Activation of PPARδ: from computer modeling to biological effects. British J. Pharmacology. 2014, 172, 754-770.

[10] Benjamin, P.F.; Steven, M. Modulators of the Nuclear Receptor Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ or RORc). J. Med. Chem. 2014, 57, 5871-5892.

[11] Mani, R.M.; Michael, H.; Miriam, S.B.; Artem, C.; Paul, S.R. Orphan nuclear receptors as drug targets for the treatment of prostate and breast cancers. Cancer Treat. Rev. 2014, 40, 1137-1152.

[12] Li, S.Z.; Shu, Q.W.; Wei, R.X.; Run, L.W.; Jing, F.W. Scffold-Based Pan-Agonist Design for the PPARα, PPARβ and PPARγ Receptors. PLoS One. 2012, 7, 48453.

[13] Antonio, C.; Marco, G.; Mariagiovanna, P.; Mario, D.R.; Luca, P.; Giuseppe, F.; Antonio, L.; Paolo, T.; Giuseppe, C.; Antonio, L.; Federica, G.; Maurizio, C.; Fulvio, L. Molecular determinants for nuclear receptors selectivity: Chemometric analysis, dockings and site-directed mutagenesis of dual peroxisome proliferator-activated receptors α/γ agonists. Eur. J. Med. Chem. 2013, 63, 321-332.

[14] Sergio, H.F.; Juan, J.R.E.; Samuel, E.S.; Julio, C.A.P.; Rubén, R.R.; Francisco, J.A.A.; Jesús V.H.R.; Hermenegilda, M.D.; Daniel, D.C.; Gabriel, N.V. Discovery of Thiazolidine-2,4-Dione/Biphenylcarbonitrile Hybrid as Dual PPARα/γ Modulator with Antidiabetic Effect: In vitro, In Silico and In vivo Approaches. Chem. Biol. Drug Des. 2013, 81, 474-483.

[15] Reeba, K.V.; Jagadheshan, H.; Juluri, S.; Cynthia, G.; Ravi, K.; Babu, P.M.; Ramanujam, R.; Ranjan, C. DRF2655: A unique molecule that reduces body weight and ameliorates metabolic abnormalities. Obes. Res. 2003, 11, 2.

[16] Cheng, X.; Li, L.W.; Hong, Y.L.; Xing, B.Z.; Ying, L.C.; Song, L. C333H, a novel PPARα/γ dual agonist, has beneficial effects on insulin resistance and lipid metabolism. Acta Pharmacol. Sin. 2006, 27, 223-228.

[17] Federica, G.; Marco, G.; Nico, M.; Omar, M.; Uliano, G.; Gianpaolo, R.; Adriana, M.; Gaia, C.; Antonio, L.; Fulvio, L.; Giorgio, P.; Antonio, L.; Donatella, C.; Emma, D.F.; Krister, B.; Maurizio, C. LT175 is a novel PPARα/γ ligand with potent insulin-sensitizing effects and reduced adipogenic properties. J. Biol. Chem. 2014, 289, 6908-6920.

[18] Laghezza, A.; Pochetti, G.; Lavecchia, A.; Fracchiolla, G.; Faliti, S.; Piemontese, L.; Di Giovanni, C.; Iacobazzi, V.; Infantino, V.; Montanari, R.; Capelli, D.; Tortorella, P.; Loiodice, F. New 2-(Aryloxy)-3-phenylpropanoic Acids as Peroxisome Proliferator-Activated Receptor α/γ Dual Agonists Able To Upregulate Mitochondrial Carnitine Shuttle System Gene Expression. J. Med. Chem. 2012, 56, 60-72.

[19] Mukul, R.J.; Suresh, R.G.; Chitrang, T.; Bibhuti, B.; Akshyaya, R.; Geeta, V.; Purvi, V.; Ramchandra, R.; Pankaj, R.P. Saroglitazar. a novel PPARα/γ agonist with predominant PPARα activity, shows lipid-lowering an insulin-sensitizing effects in preclinical models. Pharma. Res. Perspect. 2015, 3, e00136.

[20] Aravind, S.; Banshi, S.; Bhavana, S. Saroglitazar for the treatment of hypertriglyceridemia in patients with type 2 diabetes: current evidence. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2015, 8, 189-196.

[21] Rajendra, H.J.; Kevinkumar, K.; Mukul, R.J.; Harilal, P. Pharmacokinetics, safety, and Tolerability of Saroglitazar (ZYH1), a Predominantly PPARα Agonist with Moderate PPARγ Agonist Activity in Healthy Human Subjects. Clin. Drug Investig. 2013, 33, 809-816.

[22] Letizia, G.; Alessandra, D.; Antonella G.; Alessandra, A.; Barbara, D.F.; Marialuigia, F.; Pasquale, L.; Cristina, M.; Rosa, A. Synthesis and structure-activity relationships of fibrate-based analogues inside PPARs. Bioorg. Med. Chem. Lett. 2012, 22, 7662-7666.

[23] Jademilson, C.D.S.; Amanda, B.; Letizia, G.; Alessandra, A.; Barbara, D.F.; Rosa, A.; Igor, P. Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor α/γ. J. Struct. Biol. 2015, 191, 332-340.

[24] Min, H.P.; Ji, Y.P.; Hye, J.L.; Dae, H.K.; Daeui, P.; Hyoung, O.J.; Chan, H.P.; Pusoon, C.; Hyung, R.M.; Hae, Y.C. Potent Anti-Diabetic Effects of MHY908, a Newly Synthesized PPARα/γ Dual Agonist in db/db Mice. PLoS One. 2013, 8, e78815.

[25] Yoshihiro, S.; Katsuji, K.; Mitsuhiro, Y.; Kenji, Y.; Kiyoshi, C.; Hiromichi, T.; Chiyuki, A.; Mayumi, O.; Mina, N.; Hideo, K.; Yoshimasa, K.; Hiroyuki, U. Synthesis and Structure-Activity Relationships of Novel Zwitterionic Compounds as Peroxisome Proliferator Activated Receptor α/γ Dual Agonists with Improved Physicochemical Properties. Chem. Pharm. Bull. 2013, 61, 1248-1263.

[26] Yoshihiro, S.; Katsuji, K.; Mitsuhiro, Y.; Hideo, K.; Hiroyuki, U. Design, synthesis and evaluation of novel zwitterionic compounds as PPARα/γ dual agonists. Bioorg. Med. Chem. Lett. 2012, 22, 7075-7079.

[27] Yoshihiro, S.; Toshimasa, Y.; Masato, I.; Miki, O.I.; Ryo, N.; Yuki, O.; Yoshichika, Y.; Koichiro, T.; Kohjiro, U.; Takashi, K. A Novel Peroxisome Proliferator-activated Receptor (PPAR) α Agonist and PPARγ Antagonist, Z-551, Ameliorates High-fat Diet-induces Obesity and Metbolic Disorders in Mice. J. Biol. Chem. 2015, 290, 14567-14581.
[28] Danny, I.; Julia, W.; Arun, J.S. Treatment Options for Nonalcoholic Steatohepatitis. Expert Opin. Drug Saf. 2017, 1474-0338.

[29] Remy, H.; Lesley, J.M.; Bertrand, C.; Benoit, N.; Géraldine, R.; Philippe, D.; Valérie, D.; Dean, W.H.; Bart, S. The dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 exerts anti-diabetic effects in db/db mice without peroxisome proliferator-activated receptor gamma-associated adverse cardiac effects. Diabetes Vasc. Dis. Re. 2014, 11, 440-447.

[30] Hong, C.; Beatriz, D.; Ling, Q.; Xianglin, R.; Shari, L.C.; Bryan, B.; Brian, R. B.; Jesper, G.

Cevoglitazar, a Novel Peroxisome Proliferator-Activated Receptor-α/γ Dual Agonist, Potently Reduces Food Intake and Body Weight in Obese Mice and Cynomolgus Monkeys. Endocrinology. 2010, 151, 3115-3124.

[31] Kazuya, O.; Satoru, A.; Kenji, T.; Masaki, F.; Michiko, S.; Hikaru, K.; Masayasu, K.; Hiroaki, S. 2-Acyl-tetra-hydroisoquinoline-3-carboxylic Acids: Lead Compounds with Triple Actions, Peroxisome Proliferator-Activated Receptor α/γ Agonist and Protein-Tyrosine Phosphatase 1 B Inhibitory Activities. Chem. Pharm. Bull. 2011, 59, 876-879.

[32] Hee, O.H.; Jong, S.K.; Seung, H. K.; Ok, P.K.; Kyoung, H.K.; Sang, K.J.; Gwong, H.C.; Hyeon, J.Y.; Geun, T.K. Design and Synthesis of Oxime Ethers of β-Oxo-γ-phenylbutanoic Acids as PPARα and-γ Dual Agonists. B. Kor. Chem. Soc. 2012, 33, 1979-1982.

[33] Fresno, N.; Macias-Gonzalez, M.; Torres-Zaguirre, A.; Romero-Cuevas, M.; Sanz-Camacho, P.; Elguero, J.; Pavon, F.J.; Rodriguez, D.F.; Goya, P.; Perez-Fernandez, R. Novel Oxazolidinone-Based Peroxisome Proliferator Activated Receptor Agonists: Molecular Modeling, Synthesis, and Biological Evaluatioin. J. Med. Chem. 2015, 58, 6639-6652.

[34] Shogo, O.; Ryuta, S.; Tomomi, N.Y.; Minoru, I.; Makoto, M.; Yuichi, H.; Takao, Y. Structure-activity relationship studies of non-carboxylic acid peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists. Bioorg Med. Chem. Lett. 2016, 24, 5455-5461.

[35] Ryuta, S.; Shogo, O.; Tomomi, N.Y.; Minoru, I.; Makoto, M.; Yuichi, H.; Takao, Y. Switching subtype-selectivity: Fragment replacement strategy affords novel class of peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists. Bioorg Med. Chem. Lett. 2017, 27, 3131-3134.

[36] Daichi, E.; Toshimasa, I.; Yui, A.; Tomoko, S.; Keiko, Y. 17-OxoDHA is a PPARα/γ dual covalent modifier and agonist. Acs. Chem. Boil. 2016, 11, 2447-2455.

[37] Vinicius, G.M.; Marie, T.; Alessandro, S.N.; Kathia, M.H. Struture-Based Virtual Screening and Discovery of New PPARδ/γ Dual Agonist and PPARδ and PPARγ Agonists. PLoS One. 2015, 10, e0118790.

[38] Ying, M.; Shu, Q.W.; Wei, R.X.; Run, L.W.; Kuo, C.C. Design Novel Dual Agonists for Treating Type-2 Diabetes by Targeting Peroxisome Proliferator-Activated Receptors with Core Hopping Approach. PLoS One. 2012, 7, e38546.

[39] Lei, L.; Ying, M.; Run, L.W.; Wei, R.X.; Shu, Q.W.; Kuo, C.C. Find novel dual-agonist drugs for treating type 2 diabetes by means of cheminformatics. Drug Des. Dev. Ther. 2013, 7, 279-288.

[40] Nobuyasu, M.; Kanae, G.; Hiroyuki, M.; Munekazu, I.; Teruo, K.; Nobuyuki, T.; Yukihiro, A.; Hideki, T. γ-Mangostin from Garcinia Mangostana Pericarps as a Dual Agonist That Activates Both PPARα and PPARδ. Biosci. Bio. Biochem. 2013, 77, 2430-2435.

[41] Li, F.; Huan, L.; Zhijian, X.; Zhuo, Y.; Guoxin, D.; Yu, Z.; Lijing, Y.; Kaifeng, H.; Weiliang, Z.; Qingchun, T.; Kaixian, C.; Fujiang, G.; Cheng, H.; Yiming, L. Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice. Diabetologia. 2016, 59, 1276-1286.

[42] WooJung, L.; Goo, Y.; Min, C. K.; Hak, C. K.; Gyu-Un, B.; Young, K.K.; Su-Nam, K. 5,7-Dihydroxy-6-geranylflavanone improves insulin sensitivity through PPARα/γ dual activation. Int. J. Mol. Med. 2016, 37, 1397-1404.

[43] Wang, X.; Wang, G.; Shi, Y.; Sun, L.; Gorczynski, R.; Li, Y.J.; Xu, Z.; Spaner, D.E. PPAR-delta promotes survival of breast cancer cells in harsh metabolic conditions. Oncogenesis. 2016, 5, e232.

[44] Jihan, Y.; Mostafa, B. Peroxisome proliferator-activated receptors and cancer: challenges and opportunities. Br. J. Pharmacol. 2011, 164, 68-82.

[45] Rolf, M. PPARβ/δ in human cancer. Biochimie. 2017, 136, 90-99.

[46] Maria, G.B.; Jane, A.M. Targeting PPAR receptors in the airway for the treatment of inflammatory lung disease. Br. J. Pharmacol. 2009, 158, 994-1003

[47] Min, H.P.; Ji, Y.P.; Hye, J. L.; Dae, H.K.; Ki, W.C.; Daeui, P.; Hyoung, O.J.; Hye, R.K.; Chan, H.P.; So, R.K.; Pusoon, C.; Young, J.B.; Hyung, R.M.; Hae, Y.C. The Novel PPAR α/γ Dual Agonist MHY966 Modulates UVB-Induced Skin Inflammation by Inhibiting NF-kB Activity. PLoS One. 2013, 8, e76820.
[48] Wai, S.C.; Xiao, Y.T.; Wing, T.W.; Yu, H. The peroxisome proliferator-activated receptors in cardiovascular diseases: experimental benefits and clinical challenges. Br. J. Pharmacol. 2014, 172, 5512-5522.

PPAR激动剂的开发与应用

The development and application of peroxisome proliferator-activated receptor (PPAR) modulator

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 2

编辑推荐

Metrics

本文评价

[1]	杨婧, 王鑫, 王子惠, 于晓佳, 王华光, 朱莹, 李博宇, 邱爽, 安卓玲. 补充维生素D对代谢综合征的影响: 一项回顾性研究[J]. 中国药学(英文版), 2023, 32(3): 200-206.
[2]	都晓辉, 杨宏艳, 王涛, 崔红霞, 林宇, 李宏铃. 基于网络药理学和分子对接技术解读川皮苷改善代谢综合征的作用机制[J]. 中国药学(英文版), 2022, 31(11): 803-823.