基于AGEs交联结构逆转血管硬化化合物的设计、合成和生物活性评价
|
摘要
本文以AGEs交联为靶点，进行逆转老年性和糖尿病型血管硬化药物的研
究。根据先导化合物ALT-711的作用机理和结构特征，设计新类型的虚拟先导优
化组合化合物库，采用MOPAC方法计算活性位点的负净电荷，对化合物库进行
虚拟筛选，确定优选化合物；构建虚拟先导发现组合库，采用DiverseSolution的
BCUT描述符定义类药性分子的化学空间和活性分子的化学空间，并进行多样性
和类药性评价。
基于上述设计思想，合成硒唑类化合物2个、硒吩类化合物11个、噻吩类
化合物10个和咪唑并硒唑类化合物18个，共计四大类41个化合物。化合物的
结构都经IR、1HNMR、MS和元素分析等确证。在合成研究中发现一步法合成
2-氨基硒唑的新方法和一步法合成咪唑并硒唑类化合物的新方法，能够缩短反应
步骤，提高产率，适合于组合化学大规模平行合成。
完成化合物体外裂解AGEs的活性研究，结果表明有20个化合物在0． 1mmol
浓度下，17个化合物在0． 01或者0． 001mmol浓度下裂解AGE-BSA-胶原交联结
构的能力优于阳性化合物ALT711。体内试验表明化合物ZW1能够显著降低体内
RBC-IgG交联的含量；显著降低总外周阻力，提高全身动脉顺应性和改善胶原蛋
白对水解酶的敏感性。初步急性毒性试验研究表明优选化合物ZW1，ZW6，ZW7，
ZW20， ZW21和ZW22均低于阳性药物ALT711。
构效关系分析结果表明咪唑并硒唑类化合物结构中C9，N10和Se14上的电
荷密度和裂解能力密切相关，N10位是可能的质子化位点；季胺盐类化合物分子
的最低空轨道和次一级空轨道的差值(△L)对化合物的裂解活性有着重要作用；
C2的净电荷对活性也至关重要， 2位上负电荷密度越大，化合物的裂解活性越
强，提示在C2上引入对其净电荷负值起贡献的基团将会使化合物的裂解活性增
强。
在基于KBase的软件平台上，构建了季胺盐类目标化合物结构和裂解活性的
定量构效关系(QSAR)模型。基于描述符的QSAR方程结果表明化合物的裂解
活性和Charg2、 QV、I和JT四种描述符代表的性质密切相关；基于碎片的QSAR
方程结果表明四种主要的结构碎片对裂解活性起重要的贡献;建立的模型预测
18个己知的化合物的裂解活性，结果与其实验值能够较好吻合。两个QSAR模
型的建立为快速预测化合物的活性和对虚拟组合化合物库进行筛选提供可信工
具;提供了先导化合物优化的策略。
本文通过设计、合成和生物活性研究，优选出候选化合物ZWI，该化合物
具有明显的裂解AGES交联结构能力，对由AGEs交联结构引起的糖尿病大鼠动
脉硬化症状具有明显改善作用，毒性较低，可以作为逆转老年性和糖尿病型血管
硬化的候选药物进一步研究。
We designed new drugs reversing arterial stiffening in aging and diabetes targeted AGEs crosslinks. According to the proposed mechanism of breaking of AGEs crosslinks and ALT711's structure characteristics, we designed new lead optimization visual combinatorial libraries, and visually screened the libraries by calculating the charge using MOPAC. The results led to compound ZW1 with high cleavage in vivo and in vitro. We also build lead discovery visual combinatorial libraries, and defined different chemical space of the compounds in libraries.
Based on our design, 2, 11, 10, 18 compounds belong to selenazole, selenophen, thiophene and imidazole[2,1-b]selenazole respectively have been synthesized and the structure of 41 compounds have been identified by IR, 'HNMR.and MS. A novel one-pot synthesis which avoided high-toxic and unstable starting material, selenourea and was easy to operate had been used in synthesis of 2-amino-l, 3-selenazoles; a new one-pot method of synthesis of imidazole[2,l-b]selenazole had been also developed. Both were feasible in parallel synthesis of combinatorial libraries.
The results in vitro assay indicated that the breaking ratio of 20 compounds at 0.1mmol and 17 compounds at O.lmmol was higher than that of ALT711's. The in vivo study with compound ZW1 had resulted in improvement in the elasticity of stiffened vascular and increment of the solubility of diabetic tail tendon collagen.
The relationship between the structure and activities of the compounds have been studied by Ab initio calculation. The QSAR model of imidazole[2,l-b]selenazole showed that there was a good multivariate linear relationship between the activity and the charge of C9,N10 and Se14 ; the QSAR model of others showed that the activities will increase attributing to the L or the charge of C2.
The knowledge-based quantitative structure and activities relationships were used to predict the cleavage ability of AGEs crosslinks breakers. One of the Kbase QSAR
models showed that there was a good multivariate linear relationship between the activity and four major indices; the other one showed that four major fragments could enhance the activity of AGEs cleavage. 18 compounds' cleavage could be accurately predicted by the model. Both QSAR models could be used in synthetic strategies during lead optimization and new vitual libraries prediction.
Overall, the design, synthesis and screening of AGEs Cross-links breakers have been researched . The new compound ZW1 have potent ability of decreasing AGEs crosslinks in diabetic rat, improving the existing vascular and myocardial stiffness and was worth to further research as a candidate new drug.
究。根据先导化合物ALT-711的作用机理和结构特征，设计新类型的虚拟先导优
化组合化合物库，采用MOPAC方法计算活性位点的负净电荷，对化合物库进行
虚拟筛选，确定优选化合物；构建虚拟先导发现组合库，采用DiverseSolution的
BCUT描述符定义类药性分子的化学空间和活性分子的化学空间，并进行多样性
和类药性评价。
基于上述设计思想，合成硒唑类化合物2个、硒吩类化合物11个、噻吩类
化合物10个和咪唑并硒唑类化合物18个，共计四大类41个化合物。化合物的
结构都经IR、1HNMR、MS和元素分析等确证。在合成研究中发现一步法合成
2-氨基硒唑的新方法和一步法合成咪唑并硒唑类化合物的新方法，能够缩短反应
步骤，提高产率，适合于组合化学大规模平行合成。
完成化合物体外裂解AGEs的活性研究，结果表明有20个化合物在0． 1mmol
浓度下，17个化合物在0． 01或者0． 001mmol浓度下裂解AGE-BSA-胶原交联结
构的能力优于阳性化合物ALT711。体内试验表明化合物ZW1能够显著降低体内
RBC-IgG交联的含量；显著降低总外周阻力，提高全身动脉顺应性和改善胶原蛋
白对水解酶的敏感性。初步急性毒性试验研究表明优选化合物ZW1，ZW6，ZW7，
ZW20， ZW21和ZW22均低于阳性药物ALT711。
构效关系分析结果表明咪唑并硒唑类化合物结构中C9，N10和Se14上的电
荷密度和裂解能力密切相关，N10位是可能的质子化位点；季胺盐类化合物分子
的最低空轨道和次一级空轨道的差值(△L)对化合物的裂解活性有着重要作用；
C2的净电荷对活性也至关重要， 2位上负电荷密度越大，化合物的裂解活性越
强，提示在C2上引入对其净电荷负值起贡献的基团将会使化合物的裂解活性增
强。
在基于KBase的软件平台上，构建了季胺盐类目标化合物结构和裂解活性的
定量构效关系(QSAR)模型。基于描述符的QSAR方程结果表明化合物的裂解
活性和Charg2、 QV、I和JT四种描述符代表的性质密切相关；基于碎片的QSAR
方程结果表明四种主要的结构碎片对裂解活性起重要的贡献;建立的模型预测
18个己知的化合物的裂解活性，结果与其实验值能够较好吻合。两个QSAR模
型的建立为快速预测化合物的活性和对虚拟组合化合物库进行筛选提供可信工
具;提供了先导化合物优化的策略。
本文通过设计、合成和生物活性研究，优选出候选化合物ZWI，该化合物
具有明显的裂解AGES交联结构能力，对由AGEs交联结构引起的糖尿病大鼠动
脉硬化症状具有明显改善作用，毒性较低，可以作为逆转老年性和糖尿病型血管
硬化的候选药物进一步研究。
We designed new drugs reversing arterial stiffening in aging and diabetes targeted AGEs crosslinks. According to the proposed mechanism of breaking of AGEs crosslinks and ALT711's structure characteristics, we designed new lead optimization visual combinatorial libraries, and visually screened the libraries by calculating the charge using MOPAC. The results led to compound ZW1 with high cleavage in vivo and in vitro. We also build lead discovery visual combinatorial libraries, and defined different chemical space of the compounds in libraries.
Based on our design, 2, 11, 10, 18 compounds belong to selenazole, selenophen, thiophene and imidazole[2,1-b]selenazole respectively have been synthesized and the structure of 41 compounds have been identified by IR, 'HNMR.and MS. A novel one-pot synthesis which avoided high-toxic and unstable starting material, selenourea and was easy to operate had been used in synthesis of 2-amino-l, 3-selenazoles; a new one-pot method of synthesis of imidazole[2,l-b]selenazole had been also developed. Both were feasible in parallel synthesis of combinatorial libraries.
The results in vitro assay indicated that the breaking ratio of 20 compounds at 0.1mmol and 17 compounds at O.lmmol was higher than that of ALT711's. The in vivo study with compound ZW1 had resulted in improvement in the elasticity of stiffened vascular and increment of the solubility of diabetic tail tendon collagen.
The relationship between the structure and activities of the compounds have been studied by Ab initio calculation. The QSAR model of imidazole[2,l-b]selenazole showed that there was a good multivariate linear relationship between the activity and the charge of C9,N10 and Se14 ; the QSAR model of others showed that the activities will increase attributing to the L or the charge of C2.
The knowledge-based quantitative structure and activities relationships were used to predict the cleavage ability of AGEs crosslinks breakers. One of the Kbase QSAR
models showed that there was a good multivariate linear relationship between the activity and four major indices; the other one showed that four major fragments could enhance the activity of AGEs cleavage. 18 compounds' cleavage could be accurately predicted by the model. Both QSAR models could be used in synthetic strategies during lead optimization and new vitual libraries prediction.
Overall, the design, synthesis and screening of AGEs Cross-links breakers have been researched . The new compound ZW1 have potent ability of decreasing AGEs crosslinks in diabetic rat, improving the existing vascular and myocardial stiffness and was worth to further research as a candidate new drug.
引文
[1] Biernaus A, Hofmann MA, Ziegler R, et al. AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept[J] . Cardiovasc Res, 1998, 37: 586-600 .
[2] Castellani RJ, Harris PLR, Sayre LM, et al. Active glycation in neurofibrillary pathology of Alzheimer's disease: ne(Carboxymethyl)lysine and hexitol-lysine[J]. Free Rad.Biol.Med, 2001, 31:175-180
[3] Wagle D., Vasan S, Egan JJ. Thiazole, imidazole and oxazole compounds and treatments of disorders associated with protein aging[P]. WO: 01/52847, 2001-01-19
[4] Avendano GF, Agarwal RK, Bashey RI et.al. Effects of glucose intolerance on myocardial function and collagen-linked glycation[J]. Diabetes, 1999,48: 1443-1447
[5] Imanaga Y, Sakata N, Takebayashi S et al. In vivo and in vitro evidence for the glycoxidation of low density lipoprotein in human athersclerotic plaques[J]. Atherosclerosis, 2000, 150:343-355
[6] Richard EG, Darren JK and Robert CA. Novel approaches to the treatment of progressive renal disease[J]. Current Opinion in Pharmacology, 2001, 1:183-189
[7] Wolffenbuttel BH, Boulanger CM, Crijns FR, Huijberts MS, et al. Breakers of advanced glycation end products restore large arterg properties in experimental diabetes[J]. Proc Natl Acad Sci USA, 1998, 95: 4630-4634
[8] Asif M, Egan J, Vasan S, et al. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffening[J]. Proc Natl Acad Sci USA, 2000, 97: 2809-2813
[9] Vaitkevicius PV, Lane M, Spurgeon H, et al. A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys[J]. Proc Natl Acad Sci USA, 2001, 98: 1171-1175
[10] Kass DA, Shapiro EP, Kawaguchi M, et al. Improved arterial compliance by a novel advanced glycation end-product cross-link breaker[J]. Circulation, 2001, 104: 1464-1470
[11] Ulrich P, Cerami A. Protein glycation,diabetes, and aging[J]. Recent Prog Horm Res, 2001,56:1-21
[12] Cerami A, Ulrich P. Pharmaceutical intervention of advanced glycation endproducts[J]. Novartis Found Symp, 2001, 235:202-212
[13] Varagic J, Susie D, Frohlich E. Heart, aging, and hypertension[J]. Curr Opin Cardiol, 2001, 16(6) :336-41．
[14] Jaku. V., Rietbrock N. Intermediate and final products of nonenzymatic glycation . Chem. Listy, 1999, 93: 375-381．
[15] Glomb MA, Monnier VM. Mechanism of protein modification by glyoxal and glycolaldehyde, reactive intermediates of the Maillard reaction. J Biol Chem. 1995,270(17) : 10017-10026
[16] Vlassara H. Recent progress in advanced glycation end products and diabetic complications. Diabetes, 16, 1997:19-25．
[17] Schleicher E, Wieland OH. Protein glycation: Measurementand clinical relevance. J Clin Invest 1989, 27: 577-587
[18] Makita Z, Vlassara H, Cerami A, and R Bucala. Immunochemical detection of advanced glycosylation end products in vivo. J. Biol. Chem., 1992, 267:5133-5138．
[19] Radoff S, Makita Z, Vlassara H. A radio-receptor assay for advanced glycosylation end products. Diabetes, 1991, 40:1731-1738
[20] Mitsuhashi T, Vlassara H, Founds HW et.al. Standardizing the immunological measurement of advanced glycation end products using normal human serum.. J Immunol Methods, 1997, 207:79-88．
[21] Niwa T. Dialysis-related amyloidosis : pathogenesis focusing on AGE modification. Semi n Dial, 2001, 14 (2) : 123-126
[22] Brownlee M. Negative Consequences of Glycation. Metabolism ,2000 , 49 (2 Suppl1) :9-13
[23] Ikeda K, Higashi T , Sano H et al. N2-(Carboxymethyl) lysine Protein Adduct Is a Major Immunological Epitope in Proteins Modified with Advanced Glycation End Products of the Maillard Reaction. Biochemist ry, 1996 , 35 :8075-8083
[24] Raina AK. Perry G, Nunomura A et al. Histochemical and
Immunocytochemical Approaches to the Study of Oxidative Stress. Clin Chem Lab Med, 2000, 38 (2) :93 ~ 97
[25] Hou FF , Reddan DN, Seng WK, et al. Pathogenesis of β 2-microglobulin amyloidosis : role of monocytes/ macrophages. Semin Dial, 2001, 14: 135-139．
[26] Schmidt AM , Yan SD , Wautier JL et al. Activation of Receptor for advanced glycation end products. Ci re Res, 1999, 84 :489-497
[27] Renard C , Chappey O , Wautier MP et al. Recombinant Advanced Glycation End Product Receptor Pharmacokinetics in Normal and Diabetic Rats. Molecular Pharmacology , 1997, 52 :54-62
[28] Baynes JW. The role of AGEs in aging: causation or correlation[J]. Exp Gerontol, 2001, 36:1527-1537
[29] Avendano GF, Agarwal RK, Bashey RI et al. Effects of glucose intolerance on myocardial function and collagen-linked glycation[J]. Diabetes, 1999, 48(7) :1443-7
[30] Mizutani K, Ikeda K, Tsuda K et al, Inhibitor for advanced glycation end products formation attenuates hypertension and oxidative damage in genetic hypertensive rats[J]. JHypertens, 2002,20(8) : 1607-14
[31] Mizutani K, Ikeda K, Kawai Y et al, Biomechanical properties and chemical composition of the aorta in genetic hypertensive rats[J]. J Hypertens, 1999 , 17(4) :481-487
[32] Herrmann KL, McCulloch AD, Omens JH. Glycated collagen cross-linking alters cardiac mechanics in volume-overload hypertrophy[J]. Am J Physiol Heart Circ Physiol, 2003, 284(4) : 1277-1284
[33] Ferrier KE, Muhlmann MH, Baguet JP, et al. Intensive cholesterol reduction lowers blood pressure and large artery stiffening in isolated hypertension[J]. J Am Coll Cardiol, 2002, 39:1020-1025
[34] Boulanger E, Wautier MP, Wautier JL, et al. AGEs bind to mesothelial cells via RAGE and stimulate VCAM-1 expression [J]. Kidney International, 2002, 61(1) : 148-156
[35] Fumiaki Y, Hideyuki S and Takayuki S et al. An expeditious synthesis of petosidine, an advanced glycation end product. Tetrahedron, 2001, 57: 4759-4766
[36] Baynes JW. The role of AGEs in aging: causation or correlation. Experimental Gerontology. 2001, 36: 1527-1537．
[37] Nakamura K, Nakazawa Y and lenaga K. Acid-Stable Fluorescent Advanced Glycation End Products: Vesperlysines A, B, and C Are Formed as Crosslinked Products in the Maillard Reaction between Lysine or Proteins with Glucose. Biochem Biophys Res Commun, 232, 1997: 227-230
[38] Sell DR, Nelson JF, Monnier VM. Effect of chronic aminoguanidine treatment on age-related glycation, glycoxidation, and collagen cross-linking in the Fischer 344 rat[J]. J Gerontol A Biol Sci Med Sci, 2001, 56(9) :B405-411
[39] Vasan S, Foiles PG, Founds HW. Therapeutic potential of AGE inhibitors and breakers of AGE protein cross-links [J]. Expert Opin InvestigDrugs, 2001 ,10(11) : 1977-1987．
[40] Abdel-Rahman E, Bolton WK. Pimagedine: a novel therapy for diabetic nephropathy[J]. Expert Opin Investig Drugs, 2002, 11(4) :565-574
[41a] Norton GR, Candy G, Woodiwiss AJ. Aminoguanidine prevent the decreased myocardial compliance produced by streptozotocin-induced diabete mellitus [J]. Circulation, 1996,93: 1905-1912．
[41b] Corman B, Duriez, Poitevin P, et al. Aminoguanidine prevent age-related arterial stiffening and cardiac hypertrophy [J]. Proc Natl Acad Sci USA, 1998, 95: 1301-1306．
[41c] Huijberts MS, Wolffenbuttel BH, Boudier HA, et al. Aminoguanidine treatment increases elasticity and decreases fluid filtration of large arteries from diabetic rats [J]. J Clin Invest, 1993, 92: 1407-1411．
[42] Vassan S, Zhang X, Kapurniotu A, Bernhagen J, et al. An agent cleaving glucose-derived protein cross-links in vitro and in vivo[J]. Nature, 1996, 382: 275-278
[43] Vasan S, Peter F, Founds H. Therapeutic potential of breakers of advanced glycation end product-protein crosslinks[J]. Arch Biochem and Biophy, 2003, 419: 89-96．
[44] Walters WP; Stahl MT and Murcko MA. Virtual screening: an overview. Drug discover today [J], 1998, 3:160-194．
[45] Xu J; Stevenson J. Drug-like index:a new approach to measure drug-like compounds and their diversity [J]. J Chem Inf Comput.Sci, 2000, 40: 1177-1187．
[46] Pearlman RS; Smith KM. Metric validation and receptor-relevant subspace concept [J]. J Chem Inf Comput.Sci, 1999, 39: 28-35．
[47] Kudchadker MV; Zingaro RA and Irgolic KJ. Chemistry of phosphorus pentaselenide. I . Its reaction with alcohols [J]. Canadian Journal of Chemistry, 1968, 46: 1415-1424．
[48] Klayman D.L., Shine R.J. A new synthesis of selenoureas and selenothiocarbamic ester from thioureas [J]. J. Org. Chem., 1969,Vol 34(11) :3549-3551．
[49] Ruan MD., Zhang PF; Tao Y et.al. A new synthesis method for N-mono-and N,N-dissubstituted selenoamides [J]. Synthetic communications, 1996, 26(14) :2617-2623．
[50] Maeda H; Kambe N and Sonoda N. Synthesis of 1,3-selenazoles and 2-imidazolin-5-selones from isoselenocyanides [J]. Tatrahedron, 1997, 53(40) : 13667-13680．
[51] Cadogan JIG and Molina GA. A simple and convenient deamination of aromatic amines [J]. J.Chem.Soc., Perkin Trans I , 1973, 541-542．
[52] Zhong W, Zhang WN, Lil K et.al. Synthesis of 2', 4'-difluoro-α-(1H-1,2, 4-triazole-l-yl)acetophenone [J]. Chinese Journal of Pharmaceuticals. 1999, 30 (9) : 418．
[53] Raeymaekers AHM; Allewijn FTN; Vandenberk J et.al. Novel broad-spectrum anthelmintics. Tetramisole and related derivatives of 6-arylimidazo[2,l-b]thiazole [J]. J Med Chem, 1966, 9: 545-551．
[54] Kodomari M; Aosyama T and Suzuki Y. One-pot synthesis of 2-arninothiazoles using supported reagents [J]. Tetrahedron Letters, 2002, 43: 1717-1720．
[55] Jones GS; Hanson RN and Davis MA. Selenium-sulfur analogs.6． Selenoisosteres of levamisole [J]. J Heterocyclic Chem, 1983, 20: 523-526
[56] Archer S and Perianayagam. Attempt to apply lethal synthesis to the design of chemotherapeutic agents. Fluorinated 5 β-(hydroxyethyl)-4-methylthiazoles [J]. J Med Chem, 1979, 22(3) : 306-309．
[57] Kataev EG and Palkins MV [J]. Khim, 1953, 113:115
[58] Salwa EM and Raafat AEA. Synthesis and cytotoxic activity of certain new arylazothiazole containing compounds [J]. J Heterocyclic Chem, 2002, 39:1133-1138．
[59] Hanson RN, Giese RW; Davis MA; et.al. Selenium-sulfur analogues. 1． synthesis and biochemical evaluation of selenoteramisole [J]. J Med Chem, 1978, 21(5) :496-498．
[60] US.patent 5853,703．
[61] Kochakian M, Manjula BN and Egan JJ. Chronic dosing with aminoguanidine and novel advanced glycosylation end product-formation inhibitors ameliorates cross-linking of tail tendon collagen in STZ-induced diabetic rats [J]. Diabetes, 45 (12) : 1694-1700．
[62] Stegemann H, Stalder KH. Determination of hydroxy-proline [J]. Clin Chim Acta 1967;18:267-273．
[63] http://www.id-bs.com. IDBS QSAR tool theory guide, version 1． 0．
[64] Mannhold R; Van de waterbeemd H. Substructure and whole molecule approaches for calculating logP [J]. J chem. Inf Comput Sci; 2001, 15:337-354．
[65] Hawking DM. The problem of overfitting [J]. J chem. Inf Comput Sci; 2004, 44: 1-12．
[66] Rayman MR The importance of selenium to human health. Lance, 2000, 356(9225) : 233-241．
[67] Moster V. Selenoprotein P: properties, function, and regulation. Arch Bioc hem Biophys, 2000, 376(2) : 433-438．
[68] Foster LH, Sumar S. Selenium in health and disease: a review. Crit Rev Food SciNutri, 1997, 37(3) : 211-218．
[69] Behne D, Kyriakopoulos A. Mammalian selenium-containing proteins. Annu Rev Nutr, 2001,21:453-473．
[70] Brown KM, Arthur JR. Selenium, selenoproteins and human health: a review. Public Health Nutr, 2001,4(2B): 593-599．
[71] Mueckter H., Toxic effects of organoselenium compounds. Crisp Data Base National Institutes of Health. October, 2000．
[2] Castellani RJ, Harris PLR, Sayre LM, et al. Active glycation in neurofibrillary pathology of Alzheimer's disease: ne(Carboxymethyl)lysine and hexitol-lysine[J]. Free Rad.Biol.Med, 2001, 31:175-180
[3] Wagle D., Vasan S, Egan JJ. Thiazole, imidazole and oxazole compounds and treatments of disorders associated with protein aging[P]. WO: 01/52847, 2001-01-19
[4] Avendano GF, Agarwal RK, Bashey RI et.al. Effects of glucose intolerance on myocardial function and collagen-linked glycation[J]. Diabetes, 1999,48: 1443-1447
[5] Imanaga Y, Sakata N, Takebayashi S et al. In vivo and in vitro evidence for the glycoxidation of low density lipoprotein in human athersclerotic plaques[J]. Atherosclerosis, 2000, 150:343-355
[6] Richard EG, Darren JK and Robert CA. Novel approaches to the treatment of progressive renal disease[J]. Current Opinion in Pharmacology, 2001, 1:183-189
[7] Wolffenbuttel BH, Boulanger CM, Crijns FR, Huijberts MS, et al. Breakers of advanced glycation end products restore large arterg properties in experimental diabetes[J]. Proc Natl Acad Sci USA, 1998, 95: 4630-4634
[8] Asif M, Egan J, Vasan S, et al. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffening[J]. Proc Natl Acad Sci USA, 2000, 97: 2809-2813
[9] Vaitkevicius PV, Lane M, Spurgeon H, et al. A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys[J]. Proc Natl Acad Sci USA, 2001, 98: 1171-1175
[10] Kass DA, Shapiro EP, Kawaguchi M, et al. Improved arterial compliance by a novel advanced glycation end-product cross-link breaker[J]. Circulation, 2001, 104: 1464-1470
[11] Ulrich P, Cerami A. Protein glycation,diabetes, and aging[J]. Recent Prog Horm Res, 2001,56:1-21
[12] Cerami A, Ulrich P. Pharmaceutical intervention of advanced glycation endproducts[J]. Novartis Found Symp, 2001, 235:202-212
[13] Varagic J, Susie D, Frohlich E. Heart, aging, and hypertension[J]. Curr Opin Cardiol, 2001, 16(6) :336-41．
[14] Jaku. V., Rietbrock N. Intermediate and final products of nonenzymatic glycation . Chem. Listy, 1999, 93: 375-381．
[15] Glomb MA, Monnier VM. Mechanism of protein modification by glyoxal and glycolaldehyde, reactive intermediates of the Maillard reaction. J Biol Chem. 1995,270(17) : 10017-10026
[16] Vlassara H. Recent progress in advanced glycation end products and diabetic complications. Diabetes, 16, 1997:19-25．
[17] Schleicher E, Wieland OH. Protein glycation: Measurementand clinical relevance. J Clin Invest 1989, 27: 577-587
[18] Makita Z, Vlassara H, Cerami A, and R Bucala. Immunochemical detection of advanced glycosylation end products in vivo. J. Biol. Chem., 1992, 267:5133-5138．
[19] Radoff S, Makita Z, Vlassara H. A radio-receptor assay for advanced glycosylation end products. Diabetes, 1991, 40:1731-1738
[20] Mitsuhashi T, Vlassara H, Founds HW et.al. Standardizing the immunological measurement of advanced glycation end products using normal human serum.. J Immunol Methods, 1997, 207:79-88．
[21] Niwa T. Dialysis-related amyloidosis : pathogenesis focusing on AGE modification. Semi n Dial, 2001, 14 (2) : 123-126
[22] Brownlee M. Negative Consequences of Glycation. Metabolism ,2000 , 49 (2 Suppl1) :9-13
[23] Ikeda K, Higashi T , Sano H et al. N2-(Carboxymethyl) lysine Protein Adduct Is a Major Immunological Epitope in Proteins Modified with Advanced Glycation End Products of the Maillard Reaction. Biochemist ry, 1996 , 35 :8075-8083
[24] Raina AK. Perry G, Nunomura A et al. Histochemical and
Immunocytochemical Approaches to the Study of Oxidative Stress. Clin Chem Lab Med, 2000, 38 (2) :93 ~ 97
[25] Hou FF , Reddan DN, Seng WK, et al. Pathogenesis of β 2-microglobulin amyloidosis : role of monocytes/ macrophages. Semin Dial, 2001, 14: 135-139．
[26] Schmidt AM , Yan SD , Wautier JL et al. Activation of Receptor for advanced glycation end products. Ci re Res, 1999, 84 :489-497
[27] Renard C , Chappey O , Wautier MP et al. Recombinant Advanced Glycation End Product Receptor Pharmacokinetics in Normal and Diabetic Rats. Molecular Pharmacology , 1997, 52 :54-62
[28] Baynes JW. The role of AGEs in aging: causation or correlation[J]. Exp Gerontol, 2001, 36:1527-1537
[29] Avendano GF, Agarwal RK, Bashey RI et al. Effects of glucose intolerance on myocardial function and collagen-linked glycation[J]. Diabetes, 1999, 48(7) :1443-7
[30] Mizutani K, Ikeda K, Tsuda K et al, Inhibitor for advanced glycation end products formation attenuates hypertension and oxidative damage in genetic hypertensive rats[J]. JHypertens, 2002,20(8) : 1607-14
[31] Mizutani K, Ikeda K, Kawai Y et al, Biomechanical properties and chemical composition of the aorta in genetic hypertensive rats[J]. J Hypertens, 1999 , 17(4) :481-487
[32] Herrmann KL, McCulloch AD, Omens JH. Glycated collagen cross-linking alters cardiac mechanics in volume-overload hypertrophy[J]. Am J Physiol Heart Circ Physiol, 2003, 284(4) : 1277-1284
[33] Ferrier KE, Muhlmann MH, Baguet JP, et al. Intensive cholesterol reduction lowers blood pressure and large artery stiffening in isolated hypertension[J]. J Am Coll Cardiol, 2002, 39:1020-1025
[34] Boulanger E, Wautier MP, Wautier JL, et al. AGEs bind to mesothelial cells via RAGE and stimulate VCAM-1 expression [J]. Kidney International, 2002, 61(1) : 148-156
[35] Fumiaki Y, Hideyuki S and Takayuki S et al. An expeditious synthesis of petosidine, an advanced glycation end product. Tetrahedron, 2001, 57: 4759-4766
[36] Baynes JW. The role of AGEs in aging: causation or correlation. Experimental Gerontology. 2001, 36: 1527-1537．
[37] Nakamura K, Nakazawa Y and lenaga K. Acid-Stable Fluorescent Advanced Glycation End Products: Vesperlysines A, B, and C Are Formed as Crosslinked Products in the Maillard Reaction between Lysine or Proteins with Glucose. Biochem Biophys Res Commun, 232, 1997: 227-230
[38] Sell DR, Nelson JF, Monnier VM. Effect of chronic aminoguanidine treatment on age-related glycation, glycoxidation, and collagen cross-linking in the Fischer 344 rat[J]. J Gerontol A Biol Sci Med Sci, 2001, 56(9) :B405-411
[39] Vasan S, Foiles PG, Founds HW. Therapeutic potential of AGE inhibitors and breakers of AGE protein cross-links [J]. Expert Opin InvestigDrugs, 2001 ,10(11) : 1977-1987．
[40] Abdel-Rahman E, Bolton WK. Pimagedine: a novel therapy for diabetic nephropathy[J]. Expert Opin Investig Drugs, 2002, 11(4) :565-574
[41a] Norton GR, Candy G, Woodiwiss AJ. Aminoguanidine prevent the decreased myocardial compliance produced by streptozotocin-induced diabete mellitus [J]. Circulation, 1996,93: 1905-1912．
[41b] Corman B, Duriez, Poitevin P, et al. Aminoguanidine prevent age-related arterial stiffening and cardiac hypertrophy [J]. Proc Natl Acad Sci USA, 1998, 95: 1301-1306．
[41c] Huijberts MS, Wolffenbuttel BH, Boudier HA, et al. Aminoguanidine treatment increases elasticity and decreases fluid filtration of large arteries from diabetic rats [J]. J Clin Invest, 1993, 92: 1407-1411．
[42] Vassan S, Zhang X, Kapurniotu A, Bernhagen J, et al. An agent cleaving glucose-derived protein cross-links in vitro and in vivo[J]. Nature, 1996, 382: 275-278
[43] Vasan S, Peter F, Founds H. Therapeutic potential of breakers of advanced glycation end product-protein crosslinks[J]. Arch Biochem and Biophy, 2003, 419: 89-96．
[44] Walters WP; Stahl MT and Murcko MA. Virtual screening: an overview. Drug discover today [J], 1998, 3:160-194．
[45] Xu J; Stevenson J. Drug-like index:a new approach to measure drug-like compounds and their diversity [J]. J Chem Inf Comput.Sci, 2000, 40: 1177-1187．
[46] Pearlman RS; Smith KM. Metric validation and receptor-relevant subspace concept [J]. J Chem Inf Comput.Sci, 1999, 39: 28-35．
[47] Kudchadker MV; Zingaro RA and Irgolic KJ. Chemistry of phosphorus pentaselenide. I . Its reaction with alcohols [J]. Canadian Journal of Chemistry, 1968, 46: 1415-1424．
[48] Klayman D.L., Shine R.J. A new synthesis of selenoureas and selenothiocarbamic ester from thioureas [J]. J. Org. Chem., 1969,Vol 34(11) :3549-3551．
[49] Ruan MD., Zhang PF; Tao Y et.al. A new synthesis method for N-mono-and N,N-dissubstituted selenoamides [J]. Synthetic communications, 1996, 26(14) :2617-2623．
[50] Maeda H; Kambe N and Sonoda N. Synthesis of 1,3-selenazoles and 2-imidazolin-5-selones from isoselenocyanides [J]. Tatrahedron, 1997, 53(40) : 13667-13680．
[51] Cadogan JIG and Molina GA. A simple and convenient deamination of aromatic amines [J]. J.Chem.Soc., Perkin Trans I , 1973, 541-542．
[52] Zhong W, Zhang WN, Lil K et.al. Synthesis of 2', 4'-difluoro-α-(1H-1,2, 4-triazole-l-yl)acetophenone [J]. Chinese Journal of Pharmaceuticals. 1999, 30 (9) : 418．
[53] Raeymaekers AHM; Allewijn FTN; Vandenberk J et.al. Novel broad-spectrum anthelmintics. Tetramisole and related derivatives of 6-arylimidazo[2,l-b]thiazole [J]. J Med Chem, 1966, 9: 545-551．
[54] Kodomari M; Aosyama T and Suzuki Y. One-pot synthesis of 2-arninothiazoles using supported reagents [J]. Tetrahedron Letters, 2002, 43: 1717-1720．
[55] Jones GS; Hanson RN and Davis MA. Selenium-sulfur analogs.6． Selenoisosteres of levamisole [J]. J Heterocyclic Chem, 1983, 20: 523-526
[56] Archer S and Perianayagam. Attempt to apply lethal synthesis to the design of chemotherapeutic agents. Fluorinated 5 β-(hydroxyethyl)-4-methylthiazoles [J]. J Med Chem, 1979, 22(3) : 306-309．
[57] Kataev EG and Palkins MV [J]. Khim, 1953, 113:115
[58] Salwa EM and Raafat AEA. Synthesis and cytotoxic activity of certain new arylazothiazole containing compounds [J]. J Heterocyclic Chem, 2002, 39:1133-1138．
[59] Hanson RN, Giese RW; Davis MA; et.al. Selenium-sulfur analogues. 1． synthesis and biochemical evaluation of selenoteramisole [J]. J Med Chem, 1978, 21(5) :496-498．
[60] US.patent 5853,703．
[61] Kochakian M, Manjula BN and Egan JJ. Chronic dosing with aminoguanidine and novel advanced glycosylation end product-formation inhibitors ameliorates cross-linking of tail tendon collagen in STZ-induced diabetic rats [J]. Diabetes, 45 (12) : 1694-1700．
[62] Stegemann H, Stalder KH. Determination of hydroxy-proline [J]. Clin Chim Acta 1967;18:267-273．
[63] http://www.id-bs.com. IDBS QSAR tool theory guide, version 1． 0．
[64] Mannhold R; Van de waterbeemd H. Substructure and whole molecule approaches for calculating logP [J]. J chem. Inf Comput Sci; 2001, 15:337-354．
[65] Hawking DM. The problem of overfitting [J]. J chem. Inf Comput Sci; 2004, 44: 1-12．
[66] Rayman MR The importance of selenium to human health. Lance, 2000, 356(9225) : 233-241．
[67] Moster V. Selenoprotein P: properties, function, and regulation. Arch Bioc hem Biophys, 2000, 376(2) : 433-438．
[68] Foster LH, Sumar S. Selenium in health and disease: a review. Crit Rev Food SciNutri, 1997, 37(3) : 211-218．
[69] Behne D, Kyriakopoulos A. Mammalian selenium-containing proteins. Annu Rev Nutr, 2001,21:453-473．
[70] Brown KM, Arthur JR. Selenium, selenoproteins and human health: a review. Public Health Nutr, 2001,4(2B): 593-599．
[71] Mueckter H., Toxic effects of organoselenium compounds. Crisp Data Base National Institutes of Health. October, 2000．