药学学报, 2021, 56(2): 352-359
引用本文:
环奕, 彭军, 潘璇, 刘站柱, 申竹芳. 选择性PPARγ调节剂的研究新进展[J]. 药学学报, 2021, 56(2): 352-359.
HUAN Yi, PENG Jun, PAN Xuan, LIU Zhan-zhu, SHEN Zhu-fang. Updated research progress of selective PPARγ modulators[J]. Acta Pharmaceutica Sinica, 2021, 56(2): 352-359.

选择性PPARγ调节剂的研究新进展
环奕, 彭军, 潘璇, 刘站柱, 申竹芳
中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050
摘要:
噻唑烷二酮类(thiazolidinediones,TZDs)药物是目前临床使用的唯一的胰岛素增敏剂,用于2型糖尿病的治疗,其疗效确切,但众多的不良反应报道阻碍了该类药物的继续使用。过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptor γ,PPARγ)作为TZDs的已知受体,其药效作用和不良反应的相关机制得到深入的研究。为最大程度地保留PPARγ介导的胰岛素增敏药效作用,并尽量减少相关不良反应的发生,“选择性PPARγ调节剂(selective PPARγ modulators,SPPARMs)”的概念被提出和发展,并指导新药研发实践。本文就SPPARMs的定义、化合物分类及作用机制等方面对近年来取得的研究新进展作一综述,并以YR系列化合物的发现为例,展望SPPARMs的潜在应用前景。
关键词:    过氧化物酶体增殖物激活受体γ      选择性PPARγ调节剂      胰岛素抵抗      糖尿病      非酒精性脂肪肝     
Updated research progress of selective PPARγ modulators
HUAN Yi, PENG Jun, PAN Xuan, LIU Zhan-zhu, SHEN Zhu-fang
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Thiazolidinediones (TZDs) are currently the only recognized insulin sensitizers available for the clinical treatment of type 2 diabetes. Although their advantages are recognized, the profiles of numerous adverse effects hinder the continued use of these drugs. Peroxisome proliferator-activated receptor γ (PPARγ) is known as a receptor for TZDs, and its underlying mechanisms of pharmacological actions and adverse effects have been deeply explored. To maximally preserve the PPARγ-mediated insulin sensitizing effects and reduce the occurrence of related adverse effects, the concept of "selective PPARγ modulators (SPPARMs)" has been proposed and developed, guiding the development of new drugs. In this review, we summarize the recent research progress in the definition of SPPARMs, the candidate classification and the molecular underpinnings, as well as present the discovery of the YR series compounds as an example, and discuss the potential application prospects of SPPARMs.
Key words:    peroxisome proliferator-activated receptor γ    selective PPARγ modulator    insulin resistance    diabetes mellitus    nonalcoholic fatty liver disease   
收稿日期: 2020-06-19
DOI: 10.16438/j.0513-4870.2020-1022
基金项目: 国家“重大新药创制”科技重大专项(2018ZX09711-001-005-014,2018ZX09711001-003-005);中国医学科学院创新工程(2016-I2M-4-001,2017-I2M-1-010).
通讯作者: 申竹芳,Tel:86-10-83172669,E-mail:shenzhf@imm.ac.cn
Email: shenzhf@imm.ac.cn
相关功能
PDF(1033KB) Free
打印本文
0
作者相关文章
环奕  在本刊中的所有文章
彭军  在本刊中的所有文章
潘璇  在本刊中的所有文章
刘站柱  在本刊中的所有文章
申竹芳  在本刊中的所有文章

参考文献:
[1] Society CD. Guidelines for the prevention and control of type 2 diabetes in China (2017 Edition)[J]. Chin J Pract Intern Med (中国实用内科杂志), 2018, 38:292-344.
[2] Li Y, Teng D, Shi X, et al. Prevalence of diabetes recorded in mainland China using 2018 diagnostic criteria from the American Diabetes Association:national cross sectional study[J]. BMJ, 2020, 369:m997.
[3] Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes[J]. Nature, 2006, 444:840-846.
[4] Sugii S, Evans RM. Epigenetic codes of PPARgamma in metabolic disease[J]. FEBS Lett, 2011, 585:2121-2128.
[5] Savage DB. PPAR gamma as a metabolic regulator:insights from genomics and pharmacology[J]. Expert Rev Mol Med, 2005, 7:1-16.
[6] Kahn BB, McGraw TE. Rosiglitazone, PPARgamma, and type 2 diabetes[J]. N Engl J Med, 2010, 363:2667-2669.
[7] Mannucci E, Monami M, Di Bari M, et al. Cardiac safety profile of rosiglitazone:a comprehensive meta-analysis of randomized clinical trials[J]. Int J Cardiol, 2010, 143:135-140.
[8] Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes[J]. N Engl J Med, 2007, 356:2457-2471.
[9] Yessoufou A, Wahli W. Multifaceted roles of peroxisome proliferator-activated receptors (PPARs) at the cellular and whole organism levels[J]. Swiss Med Wkly, 2010, 140:w13071.
[10] Soccio RE, Chen ER, Lazar MA. Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes[J]. Cell Metab, 2014, 20:573-591.
[11] Higgins LS, Depaoli AM. Selective peroxisome proliferator-activated receptor gamma (PPARgamma) modulation as a strategy for safer therapeutic PPARgamma activation[J]. Am J Clin Nutr, 2010, 91:267S-272S.
[12] Whitehead JP. Diabetes:new conductors for the peroxisome proliferator-activated receptor gamma (PPARgamma) orchestra[J]. Int J Biochem Cell Biol, 2011, 43:1071-1074.
[13] Zhang F, Lavan BE, Gregoire FM. Selective modulators of PPAR-gamma activity:molecular aspects related to obesity and side-effects[J]. PPAR Res, 2007, 2007:32696.
[14] Higgins LS, Mantzoros CS. The development of INT131 as a selective PPARgamma modulator:approach to a safer insulin sensitizer[J]. PPAR Res, 2008, 2008:936906.
[15] Yamauchi T, Waki H, Kamon J, et al. Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes[J]. J Clin Invest, 2001, 108:1001-1013.
[16] Acton JJ 3rd, Black RM, Jones AB, et al. Benzoyl 2-methyl indoles as selective PPARgamma modulators[J]. Bioorg Med Chem Lett, 2005, 15:357-362.
[17] Miles PD, Barak Y, He W, et al. Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency[J]. J Clin Invest, 2000, 105:287-292.
[18] Yamauchi T, Kamon J, Waki H, et al. The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance[J]. J Biol Chem, 2001, 276:41245-41254.
[19] Miles PD, Barak Y, Evans RM, et al. Effect of heterozygous PPARgamma deficiency and TZD treatment on insulin resistance associated with age and high-fat feeding[J]. Am J Physiol Endocrinol Metab, 2003, 284:E618-E626.
[20] Kubota N, Terauchi Y, Miki H, et al. PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance[J]. Mol Cell, 1999, 4:597-609.
[21] Wright HM, Clish CB, Mikami T, et al. A synthetic antagonist for the peroxisome proliferator-activated receptor gamma inhibits adipocyte differentiation[J]. J Biol Chem, 2000, 275:1873-1877.
[22] Rieusset J, Touri F, Michalik L, et al. A new selective peroxisome proliferator-activated receptor gamma antagonist with antiobesity and antidiabetic activity[J]. Mol Endocrinol, 2002, 16:2628-2644.
[23] Choi JH, Banks AS, Estall JL, et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5[J]. Nature, 2010, 466:451-456.
[24] Choi JH, Banks AS, Kamenecka TM, et al. Antidiabetic actions of a non-agonist PPARgamma ligand blocking Cdk5-mediated phosphorylation[J]. Nature, 2011, 477:477-481.
[25] Kamenecka TM, Busby SA, Kumar N, et al. Potent Anti-Diabetic Actions of A Novel Non-agonist PPARgamma Ligand That Blocks Cdk5-mediated Phosphorylation[R]. Bethesda:NIH Molecular Libraries Program, 2010.
[26] Li P, Fan W, Xu J, et al. Adipocyte NCoR knockout decreases PPARgamma phosphorylation and enhances PPARgamma activity and insulin sensitivity[J]. Cell, 2011, 147:815-826.
[27] Brown KK, Henke BR, Blanchard SG, et al. A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat[J]. Diabetes, 1999, 48:1415-1424.
[28] Gregoire FM, Zhang F, Clarke HJ, et al. MBX-102/JNJ39659100, a novel peroxisome proliferator-activated receptor-ligand with weak transactivation activity retains antidiabetic properties in the absence of weight gain and edema[J]. Mol Endocrinol, 2009, 23:975-988.
[29] Chandalia A, Clarke HJ, Clemens LE, et al. MBX-102/JNJ39659100, a novel non-TZD selective partial PPAR-gamma agonist lowers triglyceride independently of PPAR-alpha activation[J]. PPAR Res, 2009, 2009:706852.
[30] Kintscher U, Goebel M. INT-131, a PPARgamma agonist for the treatment of type 2 diabetes[J]. Curr Opin Investig Drugs, 2009, 10:381-387.
[31] Motani A, Wang Z, Weiszmann J, et al. INT131:a selective modulator of PPAR gamma[J]. J Mol Biol, 2009, 386:1301-1311.
[32] Dunn FL, Higgins LS, Fredrickson J, et al. Selective modulation of PPARgamma activity can lower plasma glucose without typical thiazolidinedione side-effects in patients with type 2 diabetes[J]. J Diabetes Complicat, 2011, 25:151-158.
[33] DePaoli AM, Higgins LS, Henry RR, et al. Can a selective PPARgamma modulator improve glycemic control in patients with type 2 diabetes with fewer side effects compared with pioglitazone?[J]. Diabetes Care, 2014, 37:1918-1923.
[34] Frkic RL, He Y, Rodriguez BB, et al. Structure-activity relationship of 2,4-dichloro-N-(3,5-dichloro-4-(quinolin-3-yloxy)phenyl)benzenesulfonamide (INT131) analogs for PPARgamma-targeted antidiabetics[J]. J Med Chem, 2017, 60:4584-4593.
[35] Bolten CW, Blanner PM, McDonald WG, et al. Insulin sensitizing pharmacology of thiazolidinediones correlates with mitochondrial gene expression rather than activation of PPAR gamma[J]. Gene Regul Syst Biol, 2007, 1:73-82.
[36] Poiley J, Steinberg AS, Choi YJ, et al. A randomized, double-blind, activeand placebo-controlled efficacy and safety study of arhalofenate for reducing flare in patients with gout[J]. Arthritis Rheumatol, 2016, 68:2027-2034.
[37] McWherter C, Choi YJ, Serrano RL, et al. Arhalofenate acid inhibits monosodium urate crystal-induced inflammatory responses through activation of AMP-activated protein kinase (AMPK) signaling[J]. Arthritis Res Ther, 2018, 20:204.
[38] Marciano DP, Kuruvilla DS, Boregowda SV, et al. Pharmacological repression of PPARgamma promotes osteogenesis[J]. Nat Commun, 2015, 6:7443.
[39] da Costa Leite LF, Veras Mourao RH, de Lima Mdo C, et al. Synthesis, biological evaluation and molecular modeling studies of arylidene-thiazolidinediones with potential hypoglycemic and hypolipidemic activities[J]. Eur J Med Chem, 2007, 42:1263-1271.
[40] Amato AA, Rajagopalan S, Lin JZ, et al. GQ-16, a novel peroxisome proliferator-activated receptor gamma (PPARgamma) ligand, promotes insulin sensitization without weight gain[J]. J Biol Chem, 2012, 287:28169-28179.
[41] Weidner C, de Groot JC, Prasad A, et al. Amorfrutins are potent antidiabetic dietary natural products[J]. Proc Natl Acad Sci U S A, 2012, 109:7257-7262.
[42] Weidner C, Wowro SJ, Freiwald A, et al. Amorfrutin B is an efficient natural peroxisome proliferator-activated receptor gamma (PPARgamma) agonist with potent glucose-lowering properties[J]. Diabetologia, 2013, 56:1802-1812.
[43] Shi H, Ma J, Mi C, et al. Amorfrutin A inhibits TNF-alpha-induced NF-kappaB activation and NF-kappaB-regulated target gene products[J]. Int Immunopharmacol, 2014, 21:56-62.
[44] Lavecchia A, Di Giovanni C. Amorfrutins are efficient modulators of peroxisome proliferator-activated receptor gamma (PPARgamma) with potent antidiabetic and anticancer properties:a patent evaluation of WO2014177593 A1[J]. Expert Opin Ther Pat, 2015, 25:1341-1347.
[45] Colca JR, McDonald WG, Adams WJ. MSDC-0602K, a metabolic modulator directed at the core pathology of non-alcoholic steatohepatitis[J]. Expert Opin Investig Drugs, 2018, 27:631-636.
[46] Chen Z, Vigueira PA, Chambers KT, et al. Insulin resistance and metabolic derangements in obese mice are ameliorated by a novel peroxisome proliferator-activated receptor gamma-sparing thiazolidinedione[J]. J Biol Chem, 2012, 287:23537-23548.
[47] Colca JR, VanderLugt JT, Adams WJ, et al. Clinical proof-of-concept study with MSDC-0160, a prototype mTOT-modulating insulin sensitizer[J]. Clin Pharmacol Ther, 2013, 93:352-359.
[48] Ahmadian M, Suh JM, Hah N, et al. PPARgamma signaling and metabolism:the good, the bad and the future[J]. Nat Med, 2013, 19:557-566.
[49] Nettles KW. Insights into PPARgamma from structures with endogenous and covalently bound ligands[J]. Nat Struct Mol Biol, 2008, 15:893-895.
[50] Sharabi K, Lin H, Tavares CDJ, et al. Selective chemical inhibition of PGC-1alpha gluconeogenic activity ameliorates type 2 diabetes[J]. Cell, 2017, 169:148-160.e15.
[51] Kolli V, Stechschulte LA, Dowling AR, et al. Partial agonist, telmisartan, maintains PPARgamma serine 112 phosphorylation, and does not affect osteoblast differentiation and bone mass[J]. PLoS One, 2014, 9:e96323.
[52] Colca JR, McDonald WG, Cavey GS, et al. Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)——relationship to newly identified mitochondrial pyruvate carrier proteins[J]. PLoS One, 2013, 8:e61551.
[53] Yu R, Zhou YL, Huan Y, et al. Design, synthesis, and PPARalpha/gamma agonistic activity of novel tetrahydroisoquinoline derivatives[J]. Acta Pharm Sin (药学学报), 2011, 46:311-316.
[54] Peng K, Huan Y, Liu Q, et al. Design, synthesis and antidiabetic activity of novel tetrahydrocarboline PPAR regulators[J]. Acta Pharm Sin (药学学报), 2014, 49:490-496.
[55] Huan Y, Pan X, Peng J, et al. A novel specific peroxisome proliferator-activated receptor γ (PPARγ) modulator YR4-42 ameliorates hyperglycaemia and dyslipidaemia and hepatic steatosis in diet-induced obese mice[J]. Diabetes Obes Metab, 2019, 21:2553-2563.
[56] Lam VQ, Zheng J, Griffin PR. Unique interactome network signatures for peroxisome proliferator-activated receptor gamma (PPARgamma) modulation by functional selective ligands[J]. Mol Cell Proteomics, 2017, 16:2098-2110.
[57] Huan Y, Peng J, Wang Y, et al. Establishment and application of screening methods for non-agonist PPARγ ligand] [J]. Acta Pharm Sin (药学学报), 2014, 49:1658-1664.
[58] Zheng Y, Huan Y, Liu SX, et al. PPARγ non-agonist ligand:the structure optimization based on PPARγ partial agonist[J]. Acta Pharm Sin (药学学报), 2017, 52:1424-1431.
[59] Mirza AZ, Althagafi II, Shamshad H. Role of PPAR receptor in different diseases and their ligands:physiological importance and clinical implications[J]. Eur J Med Chem, 2019, 166:502-513.
[60] Wang J, Cheng H, Sun X, et al. Research advances in peroxisome proliferator-activated receptor γ and related diseases[J]. China Modern Med (中国当代医药), 2019, 26:30-32, 36.
[61] Wen S, Su YP. Advances in research on PPARγ and antitumor effects[J]. World Latest Med Inf (世界最新医学信息文摘), 2019, 19:100-101.
[62] Shah RC, Matthews DC, Andrews RD, et al. An evaluation of MSDC-0160, a prototype mTOT modulating insulin sensitizer, in patients with mild Alzheimer's disease[J]. Curr Alzheimer Res, 2014, 11:564-573.
[63] Camejo G. Selective PPAR modulators (SPPARs) may fill the need for treatment of the atherogenic dyslipidemia of insulin resistance and type 2 diabetes:can they reduce the associated cardiac risk?[J]. Atherosclerosis, 2016, 249:224-225.
[64] Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance[J]. Annu Rev Physiol, 2010, 72:219-246.
[65] Panigrahy D, Huang S, Kieran MW, et al. PPARgamma as a therapeutic target for tumor angiogenesis and metastasis[J]. Cancer Biol Ther, 2005, 4:687-693.
相关文献:
1.王凯, 柳星峰, 李平平.胰岛素抵抗状态下肝脏脂质合成增加的研究进展[J]. 药学学报, 2020,55(2): 189-194
2.秦惠玉, 张彤, 王忠英, 陈文, 韩博.基于系统药理学的毛菊苣醇提物治疗2型糖尿病伴随非酒精性脂肪肝作用及机制研究[J]. 药学学报, 2019,54(11): 2019-2030
3.王亚男, 张晓琳, 尹震, 田金英, 李雪晨, 叶菲.双环醇对2型糖尿病KKAy小鼠治疗作用的实验研究[J]. 药学学报, 2019,54(6): 1041-1047
4.任桐, 林辰曦, 刁勇.N-(Z)-9-十八烯基-2-丙磺酰胺对2型糖尿病小鼠胰岛素抵抗的影响及其机制[J]. 药学学报, 2017,52(12): 1871-1876
5.徐彤宇, 王文飞, 徐鹏飞, 袁清艳, 刘双庆, 张童, 任桂萍, 李德山.成纤维细胞生长因子21对胰岛素抵抗缓解作用机制的研究[J]. 药学学报, 2015,50(9): 1101-1106
6.李颖萌, 范雪梅, 王义明, 梁琼麟, 罗国安.葛根芩连汤对2型糖尿病大鼠的治疗作用及其机制探讨[J]. 药学学报, 2013,48(9): 1415-1421
7.魏媛媛, 闫 冬, 阿以仙木.加帕尔, 曲珊珊, 阿吉艾克拜尔.艾萨, 帕尔哈提.克热木.石榴花多酚对糖尿病合并脂肪肝大鼠肝脏中PON表达的影响[J]. 药学学报, 2013,48(1): 71-76
8.朱升龙, 张振宇, 任桂萍, 叶贤龙, 马蕾, 于丹, 韩苗苗, 赵景壮, 张天援, 李德山.FGF21对MSG胰岛素抵抗小鼠的非酒精性脂肪肝的治疗作用及其机制研究[J]. 药学学报, 2013,48(12): 1778-1784
9.刘率男;申竹芳.糖尿病治疗新靶点糖原合成酶激酶-3抑制剂的研究进展[J]. 药学学报, 2007,42(12): 1227-1231
10.陈丽华;李卫东.脂联素与2型糖尿病和心血管疾病[J]. 药学学报, 2006,41(11): 1034-1037
11.孙素娟;申竹芳;陈跃腾;唐玲;丁世英;谢明智.结合亚油酸对胰岛素抵抗模型MSG肥胖小鼠的影响结合亚油酸对胰岛素抵抗模型MSG肥胖小鼠的影响[J]. 药学学报, 2003,38(12): 904-907
12.郭欲晓;罗谋伦;林志彬.静注卡介苗建立免疫性胰岛素抵抗模型[J]. 药学学报, 2002,37(5): 321-325