苯并硫氮杂（艹卓）类GSK 3β非ATP竞争抑制剂的设计、合成和构效关系研究
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摘要
糖原合成酶激酶3β(Glycogen Synthase Kinase 3β,GSK 3β)是一个多功能的丝氨酸/苏氨酸蛋白激酶,参与体内多种重要的生理活动,是一个理想的疾病治疗靶标。GSK 3β的小分子抑制剂可望用于治疗多种复杂疾病,如糖尿病、早老性痴呆症以及癌症等,正在成为一个新的研究热点。本课题研究目标是在前期虚拟筛选的工作基础上,寻找非ATP竞争抑制GSK 3β的活性先导化合物,并进一步通过计算机辅助药物设计方法设计并合成相应的系列结构衍生物,通过体外酶抑制活性筛选、酶动力学作用模式评价及构效关系分析,设计合成具有更高活性和选择性的GSK 3β非ATP竞争型抑制剂,并初步明确此类抑制剂的构效关系,为进一步研究治疗糖尿病、早老性痴呆症等疾病的新型药物奠定基础。
本文综述了GSK 3β抑制剂的研究进展。目前已报道的GSK 3β小分子抑制剂主要有三类：第一类是Mg2+离子竞争抑制剂,如Li+；第二类是ATP竞争性抑制剂,如马来酰亚胺类,这类抑制剂活性一般较强,但选择性较差,毒副作用较大；第三类是非ATP竞争选择性抑制剂,如噻二氮唑二酮(thiadiazolidinone, TDZD)类,这类抑制剂最大的优势就在于具有较高的选择性,其中一个化合物NP 12已进入了临床研究,显示出了良好的应用前景。
论文阐述了本课题非ATP竞争型GSK 3β抑制剂先导化合物的获得和优化过程,以及活性筛选结果。以GSK 3β晶体(PDB code:1UV5)底物结合区的关键氨基酸Arg96, Lys205和Tyr216构建了基于靶点的筛选模型,采用Autodock 3.0.5程序对Maybridge数据库中5万个分子进行虚拟筛选,得到数十个命中结构,其中打分排名前2,3,4位的化合物具有共同的结构母核苯并[b][1,4]硫氮杂草-4-(5H)酮。通过对该结构母核进行结构修饰,设计合成了6个衍生物；并经体外酶活抑制测试,从中发现了一个中等活性(IC50=47 uM)的GSK 3β抑制剂5-苄基-2-(2-呋喃基)-2,3-二氢-苯并[b][1,4]硫氮杂(?)-4(5H)-酮(CYbc),经酶促反应动力学实验确证为非ATP竞争抑制剂,以其作为先导化合物供进一步结构优化和改造。
作者根据生物电子等排原理和基团反转等经典药物结构修饰方法对先导化合物CYbc进行了多方面结构改造。设计了三条合成路线共合成了29个结构衍生物,经体外酶活测试,与先导化合物CYbc活性相当或有所提高的目标物有12个,经酶促反应动力学实验再次证实,这些新结构衍生物对GSK 3β的抑制仍保持为非ATP竞争作用；初步构效关系表明,用苯环替换先导物CYbc的2位呋喃环得到的化合物2-苯基-2,3-二氢-苯并[b][1,4]硫氮杂(?)-4(5H)-酮(HZIIca),及母核七元环内酰胺基团进行基团反转得到的化合物2-苯基-3,4-二氢-苯并[f][1,4]硫氮杂草-5(2H)-酮(HZkca)均保持了较好活性,为进一步的结构衍生提供了良好的空间。进一步以上述2-苯基-2,3-二氢-苯并[b][1,4]硫氮杂(?)-4(5H)-酮和3,4-二氢-苯并[f][1,4]硫氮杂(?)-5(2H)-酮两种母核结构为先导,进行了多种取代基团的变换,再设计合成了43个目标化合物,经体外活性测试,活性与先导物HZkca相当的化合物有7个,活性提高的化合物有10个,酶动力学实验也再次证实此类新结构活性化合物的作用模式仍然保持为非ATP竞争抑制。根据这些活性数据总结了更进一步的构效关系。
进一步选择有代表性的活性化合物HZkcd、HZkcj、HZkpa、HZkke和HZkna与GSK 3β进行了分子对接研究,表明化合物的苯环与与GSK 3β底物作用区的Phe 93有π-π堆积作用,羰基与Arg96形成氢键。
此外,作者也尝试采用手性酸对化合物HZkcw进行化学拆分,希望得到光学异构体后经重氮化和置换反应获得活性化合物HZkcj的光学纯异构体,但拆分未获成功。
本课题共设计合成了53个中间体及78个目标化合物,经Scifinder检索其中97个化合物未见报道。作者建立了基于放射配基标记液体闪烁计数法的酶活测试体系；确证了两类新结构的非ATP竞争型抑制剂,筛选出活性化合物29个,获得了此类化合物的初步构效关系,为进一步研究非ATP竞争型GSK 3β抑制剂奠定了良好基础。
Glycogen Synthase Kinase 3β(GSK 3β) is a multifunctional serine/threonine protein kinase implicated in the regulation of many physiological responses in mammalian cells by phosphorylating a variety of cytoplasmic and nuclear proteins. To date, it is approved to be a key drug target and inhibitors of GSK 3βmight have therapeutic potential for the treatment of diabetes, Alzheimer's disease and cancer. Development of GSK 3βinhibitors is already a hot spot for medicinal chemists in recent years.
There are mainly three kinds of small molecular GSK 3βinhibitors to inhibit GSK 3βactivity through three distinct mechanisms:(1) metal ion competitive inhibitors (in Mg2+ binding site), eg. Li+; (2) ATP competitive inhibitors (in ATP binding pocket), eg. maleimides as a representative; and (3) non-ATP competitive inhibitors (in substrate interaction domain), eg. thiadiazolidinones (TDZDs). The non-ATP competitive inhibitors show much higher selectivity than the other two.
Non-specific protein kinase inhibition by ATP site-directed inhibitors might have widespread effects. This is the case of the great majority of GSK 3βinhibitors discovered until now. All of them show many others kinases activities diminishing their drug development possibilities. Non-ATP-competitive GSK 3βselective inhibitors comparatively represent an efficient pathway for providing real promising drugs for therapeutic intervention. Actually, one of TDZD analogues, NP 12, is currently undergoing PhaseⅢclinical trials for Alzheimer's disease in the EU, which is the only GSK 3βinhibitor under clinical development.
The aim of our project is to find out non-ATP competitive GSK 3βactive leads based on previous virtual screening. Corresponding derivatives are to be designed, synthesized by computer-aided drug design and evaluated by in vitro GSK 3βinhibition activity test and enzyme kinetics test. Inhibitors with better selectivity and activity are to be designed and synthesized to obtain structure-activity relationships (SAR) for further research of new drugs for the treatment of diabetes, Alzheimer's and Huntington's diseases.
The thesis describes the discovery of lead compound and the modification of non-ATP competitive GSK 3βinhibitors. A virtual screening was conducted by Autodock program, which docked 50,000 drug-like small molecules of Maybridge library at the non-ATP-binding site of GSK 3β. As a result,2,3-dihydrobenzo[b][1,4] thiazepin-4(5H)-one with variable substituents ranked in the top of those selected candidates, likely to have potent inhibition of GSK 3β. Therefore 6 derivatives of these hits were synthesized. Among which,5-benzyl-2-(furan-2-yl)-2,3-dihydrobenzo-[b][1,4]thiazepin-4(5H)-one(CYbc) showed moderate inhibition of GSK 3βin vitro test (IC50:47.69±2.38μM). By catalytic reaction kinetics test, CYbc was approved to be a non-ATP competitive inhibitor of GSK 3βand taken as a novel lead compound, which is structurally different from other inhibitors of GSK 3βand worthy of further study.
Modifications of CYbc were conducted based on bioisosterism and group reversing. Twenty nine compounds, obtained from 3 synthetic routes, were subjected to in vitro test, out of which 12 with inhibition activity equivalent to or better than CYbc. These active derivatives also inhibited GSK 3βin non-ATP competitive way. Compound 5-benzyl-2-phenyl-2,3-dihydrobenzo[b][1,4]-thiazepin-4(5H)-one (HZIIca), in which furyl group in CYbc is substituted by phenyl, and compound 4-benzyl-2-phenyl-3,4-dihydrobenzo[f][1,4]-5(2H)-one(HZkca), reversing the amide group in HZIIca, are as potent as CYbc, which provides two new scaffolds with good space for modification. Forty three targets were synthesized by introducing different groups to the nitrogen atom at 5-position in the key intermediate of 2-phenyl-2,3-dihydrobenzo[b][1,4]-thiazepin-4(5H)-one (Scaffold A) or at 4-position in 2-phenyl-3,4-dihydrobenzo-[f][1,4]-5(2H)-one (Scaffold B), or replacing the phenyl group at 2-position in Scaffold B by other aromatic groups. In vitro test of inhibition of GSK 3βshowed that 7 compounds are as potent as HZkca, while 10 compounds are more potent than HZkca. Preliminary SARs were induced.
To explore the possible binding conformation, a molecular docking study of the representative compounds HZkcj, HZkcd, HZkke, HZkpa and HZkna, was performed, and the result showed that the compounds interacted well with the non-ATP-binding site of GSK 3β:the phenyl group interacts with Phe 93 byπ～πstacking, carbonyl group with Arg 96 by hydrogen bond, respectively.
In order to get enantiomers of HZkcw, from which the active compound HZkcj could be obtained via diazotization and following replacement reaction, we tied to resolute racemic HZkcw using optical acids, but the efforts were failed.
A total amount of 53 intermediates and 78 target compounds were synthesized, out of which 97 were not hited by searching of Scifinder. All of the targets were subjected to an in vitro test system established in our lab for evaluating inhibitory activity of GSK 3(3, among which 29 show activity equivalent to or better than the lead CYbc. Preliminary SARs were resulted, which is useful for further design of non-ATP competitive inhibitors of GSK 3βwith higher activity.
本文综述了GSK 3β抑制剂的研究进展。目前已报道的GSK 3β小分子抑制剂主要有三类：第一类是Mg2+离子竞争抑制剂,如Li+；第二类是ATP竞争性抑制剂,如马来酰亚胺类,这类抑制剂活性一般较强,但选择性较差,毒副作用较大；第三类是非ATP竞争选择性抑制剂,如噻二氮唑二酮(thiadiazolidinone, TDZD)类,这类抑制剂最大的优势就在于具有较高的选择性,其中一个化合物NP 12已进入了临床研究,显示出了良好的应用前景。
论文阐述了本课题非ATP竞争型GSK 3β抑制剂先导化合物的获得和优化过程,以及活性筛选结果。以GSK 3β晶体(PDB code:1UV5)底物结合区的关键氨基酸Arg96, Lys205和Tyr216构建了基于靶点的筛选模型,采用Autodock 3.0.5程序对Maybridge数据库中5万个分子进行虚拟筛选,得到数十个命中结构,其中打分排名前2,3,4位的化合物具有共同的结构母核苯并[b][1,4]硫氮杂草-4-(5H)酮。通过对该结构母核进行结构修饰,设计合成了6个衍生物；并经体外酶活抑制测试,从中发现了一个中等活性(IC50=47 uM)的GSK 3β抑制剂5-苄基-2-(2-呋喃基)-2,3-二氢-苯并[b][1,4]硫氮杂(?)-4(5H)-酮(CYbc),经酶促反应动力学实验确证为非ATP竞争抑制剂,以其作为先导化合物供进一步结构优化和改造。
作者根据生物电子等排原理和基团反转等经典药物结构修饰方法对先导化合物CYbc进行了多方面结构改造。设计了三条合成路线共合成了29个结构衍生物,经体外酶活测试,与先导化合物CYbc活性相当或有所提高的目标物有12个,经酶促反应动力学实验再次证实,这些新结构衍生物对GSK 3β的抑制仍保持为非ATP竞争作用；初步构效关系表明,用苯环替换先导物CYbc的2位呋喃环得到的化合物2-苯基-2,3-二氢-苯并[b][1,4]硫氮杂(?)-4(5H)-酮(HZIIca),及母核七元环内酰胺基团进行基团反转得到的化合物2-苯基-3,4-二氢-苯并[f][1,4]硫氮杂草-5(2H)-酮(HZkca)均保持了较好活性,为进一步的结构衍生提供了良好的空间。进一步以上述2-苯基-2,3-二氢-苯并[b][1,4]硫氮杂(?)-4(5H)-酮和3,4-二氢-苯并[f][1,4]硫氮杂(?)-5(2H)-酮两种母核结构为先导,进行了多种取代基团的变换,再设计合成了43个目标化合物,经体外活性测试,活性与先导物HZkca相当的化合物有7个,活性提高的化合物有10个,酶动力学实验也再次证实此类新结构活性化合物的作用模式仍然保持为非ATP竞争抑制。根据这些活性数据总结了更进一步的构效关系。
进一步选择有代表性的活性化合物HZkcd、HZkcj、HZkpa、HZkke和HZkna与GSK 3β进行了分子对接研究,表明化合物的苯环与与GSK 3β底物作用区的Phe 93有π-π堆积作用,羰基与Arg96形成氢键。
此外,作者也尝试采用手性酸对化合物HZkcw进行化学拆分,希望得到光学异构体后经重氮化和置换反应获得活性化合物HZkcj的光学纯异构体,但拆分未获成功。
本课题共设计合成了53个中间体及78个目标化合物,经Scifinder检索其中97个化合物未见报道。作者建立了基于放射配基标记液体闪烁计数法的酶活测试体系；确证了两类新结构的非ATP竞争型抑制剂,筛选出活性化合物29个,获得了此类化合物的初步构效关系,为进一步研究非ATP竞争型GSK 3β抑制剂奠定了良好基础。
Glycogen Synthase Kinase 3β(GSK 3β) is a multifunctional serine/threonine protein kinase implicated in the regulation of many physiological responses in mammalian cells by phosphorylating a variety of cytoplasmic and nuclear proteins. To date, it is approved to be a key drug target and inhibitors of GSK 3βmight have therapeutic potential for the treatment of diabetes, Alzheimer's disease and cancer. Development of GSK 3βinhibitors is already a hot spot for medicinal chemists in recent years.
There are mainly three kinds of small molecular GSK 3βinhibitors to inhibit GSK 3βactivity through three distinct mechanisms:(1) metal ion competitive inhibitors (in Mg2+ binding site), eg. Li+; (2) ATP competitive inhibitors (in ATP binding pocket), eg. maleimides as a representative; and (3) non-ATP competitive inhibitors (in substrate interaction domain), eg. thiadiazolidinones (TDZDs). The non-ATP competitive inhibitors show much higher selectivity than the other two.
Non-specific protein kinase inhibition by ATP site-directed inhibitors might have widespread effects. This is the case of the great majority of GSK 3βinhibitors discovered until now. All of them show many others kinases activities diminishing their drug development possibilities. Non-ATP-competitive GSK 3βselective inhibitors comparatively represent an efficient pathway for providing real promising drugs for therapeutic intervention. Actually, one of TDZD analogues, NP 12, is currently undergoing PhaseⅢclinical trials for Alzheimer's disease in the EU, which is the only GSK 3βinhibitor under clinical development.
The aim of our project is to find out non-ATP competitive GSK 3βactive leads based on previous virtual screening. Corresponding derivatives are to be designed, synthesized by computer-aided drug design and evaluated by in vitro GSK 3βinhibition activity test and enzyme kinetics test. Inhibitors with better selectivity and activity are to be designed and synthesized to obtain structure-activity relationships (SAR) for further research of new drugs for the treatment of diabetes, Alzheimer's and Huntington's diseases.
The thesis describes the discovery of lead compound and the modification of non-ATP competitive GSK 3βinhibitors. A virtual screening was conducted by Autodock program, which docked 50,000 drug-like small molecules of Maybridge library at the non-ATP-binding site of GSK 3β. As a result,2,3-dihydrobenzo[b][1,4] thiazepin-4(5H)-one with variable substituents ranked in the top of those selected candidates, likely to have potent inhibition of GSK 3β. Therefore 6 derivatives of these hits were synthesized. Among which,5-benzyl-2-(furan-2-yl)-2,3-dihydrobenzo-[b][1,4]thiazepin-4(5H)-one(CYbc) showed moderate inhibition of GSK 3βin vitro test (IC50:47.69±2.38μM). By catalytic reaction kinetics test, CYbc was approved to be a non-ATP competitive inhibitor of GSK 3βand taken as a novel lead compound, which is structurally different from other inhibitors of GSK 3βand worthy of further study.
Modifications of CYbc were conducted based on bioisosterism and group reversing. Twenty nine compounds, obtained from 3 synthetic routes, were subjected to in vitro test, out of which 12 with inhibition activity equivalent to or better than CYbc. These active derivatives also inhibited GSK 3βin non-ATP competitive way. Compound 5-benzyl-2-phenyl-2,3-dihydrobenzo[b][1,4]-thiazepin-4(5H)-one (HZIIca), in which furyl group in CYbc is substituted by phenyl, and compound 4-benzyl-2-phenyl-3,4-dihydrobenzo[f][1,4]-5(2H)-one(HZkca), reversing the amide group in HZIIca, are as potent as CYbc, which provides two new scaffolds with good space for modification. Forty three targets were synthesized by introducing different groups to the nitrogen atom at 5-position in the key intermediate of 2-phenyl-2,3-dihydrobenzo[b][1,4]-thiazepin-4(5H)-one (Scaffold A) or at 4-position in 2-phenyl-3,4-dihydrobenzo-[f][1,4]-5(2H)-one (Scaffold B), or replacing the phenyl group at 2-position in Scaffold B by other aromatic groups. In vitro test of inhibition of GSK 3βshowed that 7 compounds are as potent as HZkca, while 10 compounds are more potent than HZkca. Preliminary SARs were induced.
To explore the possible binding conformation, a molecular docking study of the representative compounds HZkcj, HZkcd, HZkke, HZkpa and HZkna, was performed, and the result showed that the compounds interacted well with the non-ATP-binding site of GSK 3β:the phenyl group interacts with Phe 93 byπ～πstacking, carbonyl group with Arg 96 by hydrogen bond, respectively.
In order to get enantiomers of HZkcw, from which the active compound HZkcj could be obtained via diazotization and following replacement reaction, we tied to resolute racemic HZkcw using optical acids, but the efforts were failed.
A total amount of 53 intermediates and 78 target compounds were synthesized, out of which 97 were not hited by searching of Scifinder. All of the targets were subjected to an in vitro test system established in our lab for evaluating inhibitory activity of GSK 3(3, among which 29 show activity equivalent to or better than the lead CYbc. Preliminary SARs were resulted, which is useful for further design of non-ATP competitive inhibitors of GSK 3βwith higher activity.
引文
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31. Salvatore Cuzzocrea, T.G., Emanuela Mazzon, et al., Thiemermann, Glycogen Synthase Kinase-3β Inhibition Reduces Secondary Damage in Experimental Spinal Cord Trauma. The Journal of Pharmacology and Experimental Therapeutics,2006.31:p.79-89.
32. Rosa, A.O., et al., Antidepressant-like effect of the novel thiadiazolidinone NP031115 in mice. Progress in Neuro-Psychopharmacology and Biological Psychiatry,2008.32(6):p. 1549-1556.
33. Conde, S., et al., Thienyl and Phenyl a-Halomethyl Ketones:New Inhibitors of Glycogen Synthase Kinase (GSK-3β) from a Library of Compound Searching. Journal of Medicinal Chemistry,2003.46(22):p.4631-4633.
34. Perez, D.I., et al., Thienylhalomethylketones:Irreversible glycogen synthase kinase 3 inhibitors as useful pharmacological tools. Bioorganic & Medicinal Chemistry,2009. 17(19):p.6914-6925.
35. Plotkin, B., et al., Insulin mimetic action of synthetic phosphorylated peptide inhibitors of glycogen synthase kinase-3. Journal of Pharmacology and Experimental Therapeutics, 2003.305(3):p.974-980.
36. Kaidanovich-Beilin, O. and H. Eldar-Finkelman, Long-term treatment with novel glycogen synthase kinase-3 inhibitor improves glucose homeostasis in ob/ob mice: molecular characterization in liver and muscle. Journal of Pharmacology and Experimental Therapeutics,2006.316(1):p.17-24.
37. Sakai, R., et al., Manzamine A, a novel antitumor alkaloid from a sponge. Journal of the American Chemical Society,1986.108(20):p.6404-6405.
38. Hamann, M., et al., Glycogen Synthase Kinase-3 (GSK-3) Inhibitory Activity and Structure-Activity Relationship (SAR) Studies of the Manzamine Alkaloids. Potential for Alzheimer s Disease. Journal of Natural Products,2007.70(9):p.1397-1405.
1. Boonen, R.A.C.M., P.v. Tijn, and D. Zivkovic, Wnt signaling in Alzheimer's disease:Up or down, that is the question. Ageing Research Reviews,2009:p.71-82
2. Leclerc, S., et al., Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors? J. Biol. Chem.,2001. 276(1):p.251-260.
3. Felix Hernandez, J.A., The role of glycogen synthase kinase 3 in the early stages of Alzheimers disease. FEBS Letters,2008.582:p.3848-3854.
4. Goate, A., et al., Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.. Nature,1991.349(6311):p.704-706.
5. Gong-Ping Liu, Y.Z., Xiu-Qing Yao, et al. Activation of glycogen synthase kinase-3 inhibits protein phosphatase-2A and the underlying mechanisms. Neurobiology of Aging, 2008.29:p.1348-1358.
6. Martin, L., et al., Inhibition of glycogen synthase kinase-3 [beta] downregulates total tau proteins in cultured neurons and its reversal by the blockade of protein phosphatase-2A. Brain research,2009.1252:p.66-75.
7. Hanger, D.P., et al., Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau:generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci Lett,1992.147(1):p.58-62.
8. Sun, X., et al., Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C100. Neurosci.Lett.,2002.321(1-2):p.61-64
9. Shuxin Hu, A.N.B., Mychica R. Jones,. et al., Frautschy, GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals. Neurobiology of Disease,2009.33:p.193-206.
10. Seong-Ho Koh, M.Y.N., Seung Hyun Kim, Amyloid-beta-induced neurotoxicity is reduced by inhibition of glycogen synthase kinase-3. Brain research,2008.1188:p.254-262.
11. Wang, W., et al., Inhibition of glycogen synthase kinase-3b protects dopaminergic neurons from MPTP toxicity. Neuropharmacology,2007.52:p.1678-1684.
12. Frame, S. and D. Zheleva, Targeting glycogen synthase kinase-3 in insulin signalling. Expert Opinion on Therapeutic Targets,2006.10(3):p.429-444.
13. Nikoulina, S.E., et al., Potential role of glycogen synthase kinase 3 in skeletall muscle insulin resistance of Type 2 diabetes. Diabetes,2000.49(2):p.263-271.
14. Eidar, F.H. and E.G. Krebs, Phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase 3 impairs insulin action. Pro Nat Acad Sci USA,1997.94(18):p. 9660-9664.
15. Cohen, P. and M. Goedert, GSK3 inhibitors:development and therapeutic potential. Nature Reviews Drug Discovery,2004.3(6):p.479-487.
16. Wagman, A.S., K..W. Johnson, and D.E. Bussiere, Discovery and development of GSK3 inhibitors for the treatment of type 2 diabetes. Current Pharmaceutical Design,2004. 10(10):p.1105-1137.
17. Alonso, M. and A. Martinez, GSK-3 inhibitors:discoveries and developments. Current Medicinal Chemistry,2004.11(6):p.755-763.
18. McManus, E.J., et al., Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis. EMBO Journal,2005.24(8):p.1571-1583.
19. Woodgett, J.R., Physiological roles of glycogen synthase kinase-3:Potential as a therapeutic target for diabetes and other disorders. Current Drug Targets:Immune, Endocrine and Metabolic Disorders,2003.3(4):p.281-290.
20. Witherington, J., et al.,5-Aryl-pyrazolo[3,4-b]pyridazines:potent inhibitors of glycogen synthase kinase-3 (GSK-3). Bioorganic & Medicinal Chemistry Letters,2003.13(9):p. 1581-1584.
21. Vestergaard, P. and R.W. Licht,50 Years with lithium treatment in affective disorders: present problems and priorities. World J Biol Psychiatry,2001.2(1):p.18-26.
22. Dajani, R., et al., Crystal Structure of Glycogen Synthase Kinase 3 [beta]:Structural Basis for Phosphate-Primed Substrate Specificity and Autoinhibition. Cell,2001.105(6):p. 721-732.
23. ter Haar, E., et al., Structure of GSK3beta reveals a primed phosphorylation mechanism. Nat Struct Biol,2001.8(7):p.593-6.
24. Fiol, C.J., et al., Formation of protein kinase recognition sites by covalent modification of the substrate. Molecular mechanism for the synergistic actionof casein kinase II and glycogen synthase kinase 3. J. Biol. Chem.,1987.262(29):p.14042-14048.
25. Ikeda, S., et al., Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3βand β-catenin and promotes GSK-3β-dependent phosphorylation of β-catenin. EMBO J.,1998.17:p.1371-1384
26. Martinez, A., et al., First Non-ATP Competitive Glycogen Synthase Kinase 3β(GSK-3β) Inhibitors:Thiadiazolidinones (TDZD) as Potential Drugs for the Treatment of Alzheimer's Disease. J. Med. Chem.,2002.45(6):p.1292-1299.
27. Castro, A., et al., Non-ATP competitive glycogen synthase kinase 3[beta] (GSK-3[beta]) inhibitors:Study of structural requirements for thiadiazolidinone derivatives. Bioorganic & Medicinal Chemistry,2008.16(1):p.495-510.
28. Plotkin, B., et al., Insulin mimetic action of synthetic phosphorylated peptide inhibitors of glycogen synthase kinase-3. Journal of Pharmacology and Experimental Therapeutics, 2003.305(3):p.974-980.
29. Kaidanovich-Beilin, O. and H. Eldar-Finkelman, Long-term treatment with novel glycogen synthase kinase-3 inhibitor improves glucose homeostasis in ob/ob mice: molecular characterization in liver and muscle. Journal of Pharmacology and Experimental Therapeutics,2006.316(1):p.17-24.
30. Mettey, Y., et al., Aloisines, a New Family of CDK/GSK-3 Inhibitors. SAR Study, Crystal Structure in Complex with CDK2, Enzyme Selectivity, and Cellular Effects. Journal of Medicinal Chemistry,2003.46(2):p.222-236.
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1. Bellassoued, M., et al., Two-Carbon Homologation of Aldehydes via Silyl Ketene Acetals: A New Stereoselective Approach to (E)-Alkenoic Acids. The Journal of Organic Chemistry, 1998.63(24):p.8785-8789.
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7. Krapcho, J., C.F. Turk, and J.J. Piala, Syntheses and pharmacological activity of compounds related to the antidepressant,5-(2-dimethylaminoethyl)-2,3-di-hydro-2-phenyl-1,5-benzo--thiazepin-4(5H)-one (thiazesim). Ⅲ. Journal of Medicinal Chemistry,1968.11(2):p.361-364.
2. Woodgett, J.R., Molecular cloning and expression of glycogen synthase kinase-3'/factor A. The EMBO Journal,1990.9(8):p.2431-2438.
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5. Goedert, P.C.a.M., GSK3 inhibitors:development and therapeutic potential. Nature Reviews Drug Discovery,2004.3:p.479-487.
6. Liu, F., et al., Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 andGSK-3[beta]. FEBS Letters,2002.530(1-3):p.209-214.
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11. Dajani, R., et al., Crystal Structure of Glycogen Synthase Kinase 3[beta]:Structural Basis for Phosphate-Primed Substrate Specificity and Autoinhibition. Cell,2001.105(6):p. 721-732.
12. Sereno, L., et al., A novel GSK-3[beta] inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo. Neurobiology of Disease,2009.35(3):p.359-367.
13. Kenneth Hughes, E.N., Simon E.Plyte, et al., Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. The EMBO Journal,1993.12(2):p. 803-808.
14. ter Haar, E., et al., Structure of GSK3beta reveals a primed phosphorylation mechanism. Nat Struct Biol,2001.8(7):p.593-6.
15. Frame, S., P. Cohen, and R.M. Biondi, A Common Phosphate Binding Site Explains the Unique Substrate Specificity of GSK3 and Its Inactivation by Phosphorylation. Molecular Cell,2001.7(6):p.1321-1327.
16. Mettey, Y., et al., Aloisines, a New Family of CDK/GSK-3 Inhibitors. SAR Study, Crystal Structure in Complex with CDK2, Enzyme Selectivity, and Cellular Effects. Journal of Medicinal Chemistry,2003.46(2):p.222-236.
17. Eve Damiens, B.B., Dominique Marie, Gerhard Eisenbrand and Laurent Meijer, Anti-mitotic properties of indirubin-3'-monoxime, a CDK/GSK-3 inhibitor:induction of endoreplication following prophase arrest. Oncogene,2001.20:p.3786-3797.
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30. Collino, M., et al., Treatment with the glycogen synthase kinase 3[beta] inhibitor, TDZD-8, affects transient cerebral ischemia/reperfusion injury in the rat hippocampus. Shock,2008.30(3):p.299-307 10.1097/SHK.0b013e318164e762.
31. Salvatore Cuzzocrea, T.G., Emanuela Mazzon, et al., Thiemermann, Glycogen Synthase Kinase-3β Inhibition Reduces Secondary Damage in Experimental Spinal Cord Trauma. The Journal of Pharmacology and Experimental Therapeutics,2006.31:p.79-89.
32. Rosa, A.O., et al., Antidepressant-like effect of the novel thiadiazolidinone NP031115 in mice. Progress in Neuro-Psychopharmacology and Biological Psychiatry,2008.32(6):p. 1549-1556.
33. Conde, S., et al., Thienyl and Phenyl a-Halomethyl Ketones:New Inhibitors of Glycogen Synthase Kinase (GSK-3β) from a Library of Compound Searching. Journal of Medicinal Chemistry,2003.46(22):p.4631-4633.
34. Perez, D.I., et al., Thienylhalomethylketones:Irreversible glycogen synthase kinase 3 inhibitors as useful pharmacological tools. Bioorganic & Medicinal Chemistry,2009. 17(19):p.6914-6925.
35. Plotkin, B., et al., Insulin mimetic action of synthetic phosphorylated peptide inhibitors of glycogen synthase kinase-3. Journal of Pharmacology and Experimental Therapeutics, 2003.305(3):p.974-980.
36. Kaidanovich-Beilin, O. and H. Eldar-Finkelman, Long-term treatment with novel glycogen synthase kinase-3 inhibitor improves glucose homeostasis in ob/ob mice: molecular characterization in liver and muscle. Journal of Pharmacology and Experimental Therapeutics,2006.316(1):p.17-24.
37. Sakai, R., et al., Manzamine A, a novel antitumor alkaloid from a sponge. Journal of the American Chemical Society,1986.108(20):p.6404-6405.
38. Hamann, M., et al., Glycogen Synthase Kinase-3 (GSK-3) Inhibitory Activity and Structure-Activity Relationship (SAR) Studies of the Manzamine Alkaloids. Potential for Alzheimer s Disease. Journal of Natural Products,2007.70(9):p.1397-1405.
1. Boonen, R.A.C.M., P.v. Tijn, and D. Zivkovic, Wnt signaling in Alzheimer's disease:Up or down, that is the question. Ageing Research Reviews,2009:p.71-82
2. Leclerc, S., et al., Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors? J. Biol. Chem.,2001. 276(1):p.251-260.
3. Felix Hernandez, J.A., The role of glycogen synthase kinase 3 in the early stages of Alzheimers disease. FEBS Letters,2008.582:p.3848-3854.
4. Goate, A., et al., Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.. Nature,1991.349(6311):p.704-706.
5. Gong-Ping Liu, Y.Z., Xiu-Qing Yao, et al. Activation of glycogen synthase kinase-3 inhibits protein phosphatase-2A and the underlying mechanisms. Neurobiology of Aging, 2008.29:p.1348-1358.
6. Martin, L., et al., Inhibition of glycogen synthase kinase-3 [beta] downregulates total tau proteins in cultured neurons and its reversal by the blockade of protein phosphatase-2A. Brain research,2009.1252:p.66-75.
7. Hanger, D.P., et al., Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau:generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci Lett,1992.147(1):p.58-62.
8. Sun, X., et al., Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C100. Neurosci.Lett.,2002.321(1-2):p.61-64
9. Shuxin Hu, A.N.B., Mychica R. Jones,. et al., Frautschy, GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals. Neurobiology of Disease,2009.33:p.193-206.
10. Seong-Ho Koh, M.Y.N., Seung Hyun Kim, Amyloid-beta-induced neurotoxicity is reduced by inhibition of glycogen synthase kinase-3. Brain research,2008.1188:p.254-262.
11. Wang, W., et al., Inhibition of glycogen synthase kinase-3b protects dopaminergic neurons from MPTP toxicity. Neuropharmacology,2007.52:p.1678-1684.
12. Frame, S. and D. Zheleva, Targeting glycogen synthase kinase-3 in insulin signalling. Expert Opinion on Therapeutic Targets,2006.10(3):p.429-444.
13. Nikoulina, S.E., et al., Potential role of glycogen synthase kinase 3 in skeletall muscle insulin resistance of Type 2 diabetes. Diabetes,2000.49(2):p.263-271.
14. Eidar, F.H. and E.G. Krebs, Phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase 3 impairs insulin action. Pro Nat Acad Sci USA,1997.94(18):p. 9660-9664.
15. Cohen, P. and M. Goedert, GSK3 inhibitors:development and therapeutic potential. Nature Reviews Drug Discovery,2004.3(6):p.479-487.
16. Wagman, A.S., K..W. Johnson, and D.E. Bussiere, Discovery and development of GSK3 inhibitors for the treatment of type 2 diabetes. Current Pharmaceutical Design,2004. 10(10):p.1105-1137.
17. Alonso, M. and A. Martinez, GSK-3 inhibitors:discoveries and developments. Current Medicinal Chemistry,2004.11(6):p.755-763.
18. McManus, E.J., et al., Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis. EMBO Journal,2005.24(8):p.1571-1583.
19. Woodgett, J.R., Physiological roles of glycogen synthase kinase-3:Potential as a therapeutic target for diabetes and other disorders. Current Drug Targets:Immune, Endocrine and Metabolic Disorders,2003.3(4):p.281-290.
20. Witherington, J., et al.,5-Aryl-pyrazolo[3,4-b]pyridazines:potent inhibitors of glycogen synthase kinase-3 (GSK-3). Bioorganic & Medicinal Chemistry Letters,2003.13(9):p. 1581-1584.
21. Vestergaard, P. and R.W. Licht,50 Years with lithium treatment in affective disorders: present problems and priorities. World J Biol Psychiatry,2001.2(1):p.18-26.
22. Dajani, R., et al., Crystal Structure of Glycogen Synthase Kinase 3 [beta]:Structural Basis for Phosphate-Primed Substrate Specificity and Autoinhibition. Cell,2001.105(6):p. 721-732.
23. ter Haar, E., et al., Structure of GSK3beta reveals a primed phosphorylation mechanism. Nat Struct Biol,2001.8(7):p.593-6.
24. Fiol, C.J., et al., Formation of protein kinase recognition sites by covalent modification of the substrate. Molecular mechanism for the synergistic actionof casein kinase II and glycogen synthase kinase 3. J. Biol. Chem.,1987.262(29):p.14042-14048.
25. Ikeda, S., et al., Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3βand β-catenin and promotes GSK-3β-dependent phosphorylation of β-catenin. EMBO J.,1998.17:p.1371-1384
26. Martinez, A., et al., First Non-ATP Competitive Glycogen Synthase Kinase 3β(GSK-3β) Inhibitors:Thiadiazolidinones (TDZD) as Potential Drugs for the Treatment of Alzheimer's Disease. J. Med. Chem.,2002.45(6):p.1292-1299.
27. Castro, A., et al., Non-ATP competitive glycogen synthase kinase 3[beta] (GSK-3[beta]) inhibitors:Study of structural requirements for thiadiazolidinone derivatives. Bioorganic & Medicinal Chemistry,2008.16(1):p.495-510.
28. Plotkin, B., et al., Insulin mimetic action of synthetic phosphorylated peptide inhibitors of glycogen synthase kinase-3. Journal of Pharmacology and Experimental Therapeutics, 2003.305(3):p.974-980.
29. Kaidanovich-Beilin, O. and H. Eldar-Finkelman, Long-term treatment with novel glycogen synthase kinase-3 inhibitor improves glucose homeostasis in ob/ob mice: molecular characterization in liver and muscle. Journal of Pharmacology and Experimental Therapeutics,2006.316(1):p.17-24.
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