β-分泌酶抑制剂的设计、合成与构效关系研究
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摘要
阿尔茨海默病(Alzheimer’s disease, AD),是一种慢性神经退行性疾病,病理特征是神经细胞内出现神经纤维缠结(neurofibrillary tangles, NFTs)和神经细胞外形成淀粉样老年斑(amyloid plaques)。目前临床主要的治疗药物,不能从根本上改变治疗状态。
β-淀粉样蛋白链式假说认为,脑内β-淀粉样多肽(β-amyloid peptides, Aβ)聚集形成老年斑,老年斑具有神经毒性,进而引起神经细胞死亡。β-淀粉样多肽由β-淀粉样前体蛋白(β-amyloid precursor protein,β-APP)先后经β-和γ-分泌酶水解而成。因此β-分泌酶(β-amyloid precursor enzyme-1, BACE1)是发现新型AD药物的药靶。
以OM99-1、OM99-2和OM00-3为代表的β–分泌酶抑制剂虽然对靶标有强的亲和力,但分子质量均为900 Da以上,在结构上属于多肽,缺乏类药特性。在β-分泌酶抑制剂的发现进程中,一个突破性的进展是Merck公司的Shawn J. Stachel等于2004年发现的磺酰胺基取代的间苯二甲酸衍生物类化合物,相继又发现了化合物CTS-21166,并且已经进入临床II期实验。
本课题基于β-分泌酶的结构,并结合文献中报道的BACE1抑制剂的结构和构效关系,借助计算机辅助药物设计,设计了两类目标化合物。用Sybyl 8.1中的Surflex模块进行分子对接研究,确定了拟合成的目标化合物。通过近二十步有机合成反应,合成了二十个异噻唑酮取代的间苯二甲酸衍生物,HPLC测定纯度均在90%以上,通过1NMR,MS等确证其结构。
本课题探讨并优化了三个关键中间体的合成路线。在化合物合成的过程中,重点探索了异噻唑酮环的合成、Suzuki偶联反应和羟乙胺中间体合成的条件。
本研究用时间分辨荧光法(Time-resolved fluorescence,TRF)检测化合物对β-分泌酶的抑制活性。利用APP/BACE1双转CHO(Chinese hamster ovary)细胞模型对10个化合物测定了抑制Aβ40产生的活性。结果发现在结构类型为V的化合物中,有4个化合物显示出对BACE1有较强的抑制活性,在1μmol·L -1抑制率大于70%,其中Va抑制BACE1的IC50值为13.7 nmol·L -1;在APP/BACE1双转CHO细胞上,该化合物在50 nmol·L -1下对Aβ40产生的抑制率为19.6%。在结构类型VI的化合物中,有8个化合物对BACE1显示了较强的抑制活性,其中VIc抑制BACE1的IC50值为8.1 nmol·L -1,在浓度10 nmol·L -1时对Aβ40产生的抑制率为43.7%;VId抑制BACE1的IC50值为73.7 nmol·L-1,在浓度10 nmol·L -1时对Aβ40产生的抑制率为58.3%。共有三个化合物的细胞模型评价结果比阳性药结果好,并即将进入动物实验模型评价。
本课题所设计的化合物,通过分子水平和细胞水平的评价,活性较好,并总结出一定的构效关系。为进一步开展化合物的设计与合成,发现活性高、选择性好并能够通过血脑屏障的BACE1抑制剂奠定了基础。
Alzheimer’s disease (AD), the neurodegenerative disorder, is the most common cause of dementia. It is characterized pathologically by the presence of intracellular neurofibrillary tangles(NFTs)and extracellular amyloid plaques. The current treatments temporarily alleviate the cognitive symptoms of the illness but cannot stop or slow down neuronal cell death or brain deterioration.
Acording to the amyloid hypothesis, accumulation of amyloid peptides(Aβ) in the brain which is the main component of senile plaques result in neuronal toxicity and cell death. Aβis produced fromβ-amyloid precursor protein (β-APP) by the sequential cleavage of theβ-andγ-secretase.β-secretase (β-amyloid cleaving enzyme-1, BACE1) has being considered to be an attractive therapeutic target for the treatment and prevention of AD.
Even though theβ-secretase inhibitors OM99-1、OM99-2 and OM00-3 have high affinity to the target, their molecular mass is over 900 Da and these compounds are belong to polypeptide structure and insufficient of drug-likeness. During the develepment process ofβ-secretase inhibitors, the breakthrough was that Shawn J. Stachel from Merck develeped sulfamide substituted isophthalic acid derivatives in 2004. One of these derivatives, CTS-21166, has been ongoing phase II clinical trials..
Based on the crystal structure of BACE1 and the structure-function relationship of BACE1 inhibitors , with the assistance of computer-aided drug design, two types of target compounds were designed. Then the compounds, which would be synthesized in this study, were selected by molecular docking (Surflex Model of Sybyl 8.1 program) against active site of BACE1. Finally, twenty target compounds of isothiazolone substituted isophthalic acid derivatives were synthesized. The purity of these compounds determined by HPLC was over 90 %. The structures of these compounds had been confirmed by 1H-NMR and MS.
Synthetic routes of three key intermediates were investigated and optimized. In the course of synthesizing these compounds, the synthetic conditions for isothiazolone substituted isophthalic acid, Suzuki coupling reaction and hydroxyethyl- amine intermediates were emphatically explored.
Time-resolved fluorescence (TRF) was used to evaluate the inhibitory activity of these compounds againstβ-secretase. Inhibitory activity of ten target compounds against Aβ40 production was determined on APP/BACE1 double transfection CHO cell. The results showed that four compounds of type V had high inhibitory activities against BACE1 with inhibitiory rate of more than 70% at the concentration of 1μmol·L -1. Compound Va had an IC50 value of 13.7 nmol·L -1. Its inhibitiory rate against Aβ40 production on APP/BACE1 double transfection CHO cell was 19.6% at the concentration of 50 nmol·L -1. Eight compounds of type VI had high inhibitory activities against BACE1. Especially compound VIc had an IC50 value of 8.1 nmol·L -1,which inhibitiory rate against Aβ40 production on APP/BACE1 double transfection CHO cell was 43.7% at the concentration of 10 nmol·L -1. Compound VId had an IC50 value of 73.7 nmol·L -1,which inhibitiory rate against Aβ40 production on APP/BACE1 double transfection CHO cell was 58.3% at the concentration of 10 nmol·L -1. Three compounds had more potent inhibitory activities against Aβ40 production on APP/BACE1 double transfection CHO cell than positive control compound, and they are ongoing for the animal model evaluation.
Compounds designed and synthesized in this study were evaluated in the molecular and cellular level . The structure-function relationship were summarized. All the work could guide the future research of designing and synthesizing novol BACE1 inhibitors which could pass the blood-brain barrier with high inhibitory activity and selectivity.
β-淀粉样蛋白链式假说认为,脑内β-淀粉样多肽(β-amyloid peptides, Aβ)聚集形成老年斑,老年斑具有神经毒性,进而引起神经细胞死亡。β-淀粉样多肽由β-淀粉样前体蛋白(β-amyloid precursor protein,β-APP)先后经β-和γ-分泌酶水解而成。因此β-分泌酶(β-amyloid precursor enzyme-1, BACE1)是发现新型AD药物的药靶。
以OM99-1、OM99-2和OM00-3为代表的β–分泌酶抑制剂虽然对靶标有强的亲和力,但分子质量均为900 Da以上,在结构上属于多肽,缺乏类药特性。在β-分泌酶抑制剂的发现进程中,一个突破性的进展是Merck公司的Shawn J. Stachel等于2004年发现的磺酰胺基取代的间苯二甲酸衍生物类化合物,相继又发现了化合物CTS-21166,并且已经进入临床II期实验。
本课题基于β-分泌酶的结构,并结合文献中报道的BACE1抑制剂的结构和构效关系,借助计算机辅助药物设计,设计了两类目标化合物。用Sybyl 8.1中的Surflex模块进行分子对接研究,确定了拟合成的目标化合物。通过近二十步有机合成反应,合成了二十个异噻唑酮取代的间苯二甲酸衍生物,HPLC测定纯度均在90%以上,通过1NMR,MS等确证其结构。
本课题探讨并优化了三个关键中间体的合成路线。在化合物合成的过程中,重点探索了异噻唑酮环的合成、Suzuki偶联反应和羟乙胺中间体合成的条件。
本研究用时间分辨荧光法(Time-resolved fluorescence,TRF)检测化合物对β-分泌酶的抑制活性。利用APP/BACE1双转CHO(Chinese hamster ovary)细胞模型对10个化合物测定了抑制Aβ40产生的活性。结果发现在结构类型为V的化合物中,有4个化合物显示出对BACE1有较强的抑制活性,在1μmol·L -1抑制率大于70%,其中Va抑制BACE1的IC50值为13.7 nmol·L -1;在APP/BACE1双转CHO细胞上,该化合物在50 nmol·L -1下对Aβ40产生的抑制率为19.6%。在结构类型VI的化合物中,有8个化合物对BACE1显示了较强的抑制活性,其中VIc抑制BACE1的IC50值为8.1 nmol·L -1,在浓度10 nmol·L -1时对Aβ40产生的抑制率为43.7%;VId抑制BACE1的IC50值为73.7 nmol·L-1,在浓度10 nmol·L -1时对Aβ40产生的抑制率为58.3%。共有三个化合物的细胞模型评价结果比阳性药结果好,并即将进入动物实验模型评价。
本课题所设计的化合物,通过分子水平和细胞水平的评价,活性较好,并总结出一定的构效关系。为进一步开展化合物的设计与合成,发现活性高、选择性好并能够通过血脑屏障的BACE1抑制剂奠定了基础。
Alzheimer’s disease (AD), the neurodegenerative disorder, is the most common cause of dementia. It is characterized pathologically by the presence of intracellular neurofibrillary tangles(NFTs)and extracellular amyloid plaques. The current treatments temporarily alleviate the cognitive symptoms of the illness but cannot stop or slow down neuronal cell death or brain deterioration.
Acording to the amyloid hypothesis, accumulation of amyloid peptides(Aβ) in the brain which is the main component of senile plaques result in neuronal toxicity and cell death. Aβis produced fromβ-amyloid precursor protein (β-APP) by the sequential cleavage of theβ-andγ-secretase.β-secretase (β-amyloid cleaving enzyme-1, BACE1) has being considered to be an attractive therapeutic target for the treatment and prevention of AD.
Even though theβ-secretase inhibitors OM99-1、OM99-2 and OM00-3 have high affinity to the target, their molecular mass is over 900 Da and these compounds are belong to polypeptide structure and insufficient of drug-likeness. During the develepment process ofβ-secretase inhibitors, the breakthrough was that Shawn J. Stachel from Merck develeped sulfamide substituted isophthalic acid derivatives in 2004. One of these derivatives, CTS-21166, has been ongoing phase II clinical trials..
Based on the crystal structure of BACE1 and the structure-function relationship of BACE1 inhibitors , with the assistance of computer-aided drug design, two types of target compounds were designed. Then the compounds, which would be synthesized in this study, were selected by molecular docking (Surflex Model of Sybyl 8.1 program) against active site of BACE1. Finally, twenty target compounds of isothiazolone substituted isophthalic acid derivatives were synthesized. The purity of these compounds determined by HPLC was over 90 %. The structures of these compounds had been confirmed by 1H-NMR and MS.
Synthetic routes of three key intermediates were investigated and optimized. In the course of synthesizing these compounds, the synthetic conditions for isothiazolone substituted isophthalic acid, Suzuki coupling reaction and hydroxyethyl- amine intermediates were emphatically explored.
Time-resolved fluorescence (TRF) was used to evaluate the inhibitory activity of these compounds againstβ-secretase. Inhibitory activity of ten target compounds against Aβ40 production was determined on APP/BACE1 double transfection CHO cell. The results showed that four compounds of type V had high inhibitory activities against BACE1 with inhibitiory rate of more than 70% at the concentration of 1μmol·L -1. Compound Va had an IC50 value of 13.7 nmol·L -1. Its inhibitiory rate against Aβ40 production on APP/BACE1 double transfection CHO cell was 19.6% at the concentration of 50 nmol·L -1. Eight compounds of type VI had high inhibitory activities against BACE1. Especially compound VIc had an IC50 value of 8.1 nmol·L -1,which inhibitiory rate against Aβ40 production on APP/BACE1 double transfection CHO cell was 43.7% at the concentration of 10 nmol·L -1. Compound VId had an IC50 value of 73.7 nmol·L -1,which inhibitiory rate against Aβ40 production on APP/BACE1 double transfection CHO cell was 58.3% at the concentration of 10 nmol·L -1. Three compounds had more potent inhibitory activities against Aβ40 production on APP/BACE1 double transfection CHO cell than positive control compound, and they are ongoing for the animal model evaluation.
Compounds designed and synthesized in this study were evaluated in the molecular and cellular level . The structure-function relationship were summarized. All the work could guide the future research of designing and synthesizing novol BACE1 inhibitors which could pass the blood-brain barrier with high inhibitory activity and selectivity.
引文
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2. Hardy J A, Higgins G A. Alzheimer’s diseases: the amyloid cascade hypothesis. Sience, 1992, 256(5054): 184?185.
3.侯佳宁,胡雅儿.阿尔茨海默病淀粉样肽级联假说及其相关基因研究进展,神经解剖学杂志, 2009, 25(1): 111?114.
4. Ghosh A K, Gemma S, Tang J.β-Secretase as a Therapeutic Target for Alzheimer’s Disease. Neurotherapeutics, 2008, 5(3): 399?408.
5. Esler W P, Wolfe M S. A portrait of Alzheimer secretases– new features and familiar faces. Science, 2001, 293(5534): 1449?1454.
6. Eugene D T, Lee H L. Therapeutic approaches to Alzheimer’s disease. Current Opinion in Chemical Biology, 2000, 4(4): 377?382.
7. Lambert M P, Barlow A K, Chromy B A, et al. Diffusible, nonfibrillar ligands derived from A beta 1?42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA, 1998,95(11): 6448– 6453.
8. Citron M.β-Secretase as a target for the treatment of Alzheimer’s disease. Journal of Neuroscience Research. 2002, 70(3): 373?379.
9. Luo Y, Bolon B, Kahn S, et al. Mice deficient in BACE1, the alzheimer’sβ-secretase,have normal phenotype and abolishβ-amyloid generation. J Molecular Neuroscience, 2001,17(2): 157?170.
10. Roberds S L,Anderson J, Basi G, et al. BACE knockout mice are healthy despite lacking the primary beta-secrerase activity in brain: implication for Alzheimer’s disease therpeutics. Human Molecular Genetics, 2001, 10(12): 1317?1324.
11. Zhong Z, Ewers M , Teipel S, et al. Levels of beta?secretase(BACE1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment. Archives General Psychiatry, 2007, 64(6): 718?726.
12. Holsinger R M, Lee J S, Boyd A, et al. CSF BACE1 activity is increased in CJD and Alzheimer disease versus [corrected] other dementias. Neurology, 2006, 67(4): 710?712.
13. Stachel S J. Progress Toward the Development of a Viable BACE-1Inhibitor. Drug Development Reseach, 2009, 70(2): 101–110.
14. Silvestri R. Boom in the Development of Non-Peptidicβ-Secretase (BACE1) Inhibitors for the Treatment of Alzheimer’s Disease. Medicinal Research Reviews, 2009, 29(2): 295–338.
15. Hamada Y, Kiso Y. Recent progress in the drug discovery of non-peptidic BACE1 inhibitors. Expert Opinion Drug Discovery, 2009, 4(4): 391–416.
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2. Hardy J A, Higgins G A. Alzheimer’s diseases: the amyloid cascade hypothesis. Sience, 1992, 256(5054): 184?185.
3.侯佳宁,胡雅儿.阿尔茨海默病淀粉样肽级联假说及其相关基因研究进展,神经解剖学杂志, 2009, 25(1): 111?114.
4. Ghosh A K, Gemma S, Tang J.β-Secretase as a Therapeutic Target for Alzheimer’s Disease. Neurotherapeutics, 2008, 5(3): 399?408.
5. Esler W P, Wolfe M S. A portrait of Alzheimer secretases– new features and familiar faces. Science, 2001, 293(5534): 1449?1454.
6. Eugene D T, Lee H L. Therapeutic approaches to Alzheimer’s disease. Current Opinion in Chemical Biology, 2000, 4(4): 377?382.
7. Lambert M P, Barlow A K, Chromy B A, et al. Diffusible, nonfibrillar ligands derived from A beta 1?42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA, 1998,95(11): 6448– 6453.
8. Citron M.β-Secretase as a target for the treatment of Alzheimer’s disease. Journal of Neuroscience Research. 2002, 70(3): 373?379.
9. Luo Y, Bolon B, Kahn S, et al. Mice deficient in BACE1, the alzheimer’sβ-secretase,have normal phenotype and abolishβ-amyloid generation. J Molecular Neuroscience, 2001,17(2): 157?170.
10. Roberds S L,Anderson J, Basi G, et al. BACE knockout mice are healthy despite lacking the primary beta-secrerase activity in brain: implication for Alzheimer’s disease therpeutics. Human Molecular Genetics, 2001, 10(12): 1317?1324.
11. Zhong Z, Ewers M , Teipel S, et al. Levels of beta?secretase(BACE1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment. Archives General Psychiatry, 2007, 64(6): 718?726.
12. Holsinger R M, Lee J S, Boyd A, et al. CSF BACE1 activity is increased in CJD and Alzheimer disease versus [corrected] other dementias. Neurology, 2006, 67(4): 710?712.
13. Stachel S J. Progress Toward the Development of a Viable BACE-1Inhibitor. Drug Development Reseach, 2009, 70(2): 101–110.
14. Silvestri R. Boom in the Development of Non-Peptidicβ-Secretase (BACE1) Inhibitors for the Treatment of Alzheimer’s Disease. Medicinal Research Reviews, 2009, 29(2): 295–338.
15. Hamada Y, Kiso Y. Recent progress in the drug discovery of non-peptidic BACE1 inhibitors. Expert Opinion Drug Discovery, 2009, 4(4): 391–416.
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