SGLT2抑制剂达格列净脱氧衍生物的研究
摘要
糖尿病是以高血糖为特征的糖、蛋白质和脂肪代谢障碍性疾病。糖尿病本身具有渐进性的本质,伴随着糖尿病渐进性的发展而出现的多种并发症严重损害了人类的健康,威胁着人类的生命安全。糖尿病造成的高血糖会导致身体组织的损坏并导致微血管病变和大血管病变,如视网膜病、肾病、神经病、中风和冠状动脉粥样化,还会诱发口腔健康、睡眠呼吸暂停以及抑制伤口的愈合和下肢的感染和坏疽等。持续性的高血糖还能加剧胰岛素抵抗并且加剧胰岛p细胞损坏,进而加速细胞凋亡。随着全球范围内糖尿病患者成逐年增加的态势,糖尿病已经成为备受人们关注的社会、经济和健康问题。
随着人们对糖尿病发病机制研究的深入而研发出适用于不同发展阶段的抗糖尿病药物,但这些药物并不能使所有的糖尿病患者达到血糖控制标准(HbA1。<7.0%)。此外,目前这些抗糖尿病药物均具有不同程度的副作用,如体重增加、低血糖、水潴留及胃肠道副作用(恶心、呕吐)等。传统的降低糖尿病患者血糖的药物大部分集中在能够提高内源性胰岛素的分泌和/或者是提高机体周围组织对胰岛素的敏感性。几乎所有的患者都在经历糖尿病造成的胰腺功能逐渐衰竭的各个阶段。因此,寻找具有新的作用机制、更加安全和更加有效的抗糖尿病药物刻不容缓。
肾脏作为以原尿形式存在的葡萄糖重吸收的器官,它对人体的葡萄糖的自稳平衡起着特别重要的作用。高血糖是糖尿病的表现形式,设计合成一种阻止葡萄糖重吸收的药物使葡萄糖在尿液中以糖尿的形式排出体外,这也是降低血糖的一种新的途径。
体内的葡萄糖大部分被小肠吸收,剩余的葡萄糖流经肾脏时被过滤到肾小球中形成原尿。当原尿流经肾小管时,位于肾近曲小管官腔上皮细胞的载体蛋白SGLTs,会耦合着钠离子和葡萄糖穿过细胞膜而重新回到到血液中。SGLTs主要包括SGLT1和SGLT2,位于肾近曲小管S1段的SGLT2耦合超过90%的葡萄糖穿过细胞膜重新回到血液循环；剩余不足10%的葡萄糖与SGLT1耦合重新回到血液循环。因此,抑制SGLT2的转运活性进而特异性地抑制葡萄糖在肾脏中的重吸收,以达到控制糖尿病患者的血糖水平。以肾脏为靶器官的抗糖尿病药物SGLT2抑制剂成为化学家和药物学家研究的热点。
本论文立足于全球范围内抗2型糖尿病药物研究现状,对已经上市和正处于各期临床阶段的SGLT2抑制剂分子结构进行剖析,发现当前的SGLT2抑制剂绝大部分以dapagliflozin为先导化合物进行结构修饰。Canagliflozin、ipragliflozin和empagliflozin以dapagliflozin为模板,保持糖环片段结构不变,改变糖苷的配基芳香环片段；LX4211和PF-04971729则保持糖苷配基二苯甲烷结构不变,对糖环片段做了细微的改动；tofogliflozin和TS-071则对糖环片段和糖苷配基均作出不同程度地改造,但却依然遵循糖环片段结构相似性和配基部分芳香性即保持亲脂性合适。
上述三大类SGLT2抑制剂设计的出发点都是围绕着dapagliflzin,做出糖苷配基或/和糖环部分的改变。迄今为止,还没有任何一个药物研发者阐述糖环片段的羟基对于药物构效关系所起的作用。
本论文选择dapagliflozin作为先导化合物,对其糖环片段的四个羟基进行逐渐单一脱氧和组合脱氧,进而明确羟基对药物构效关系的影响。通过对脱氧产物D6(6-deoxydapagliflozin)、D4(4-deoxydapagliflozin)、D3(3-deoxydapagliflozin)和D2(2-deoxydapagliflozin)的生物活性评价(体外活性评价和体内活性评价),明确了dapagliflozin糖环片段的四个羟基对药物构效关系的影响。
6-OH的存在反而降低了先导化合物dapagliflozin的生物活性,IC50=0.67nMagainst hSGLT2vs1.16nM for dapagliflozin。换言之,6-OH脱氧产物D6与受体SGLT2转运蛋白的结合力较dapagliflozin增强,进而导致SGLT2耦合葡萄糖的能力降低,减少了葡萄糖在肾脏的重吸收而增加了尿糖的排泄。
4-OH脱氧产物的SGLT2抑制活性几乎完全丧失,说明4-OH在先导化合物dapagliflozin与受体SGLT2转运蛋白的亲和力上起着无可取代的作用。
3-OH脱氧产物的SGLT2能力较dapagliflozin有所下降,IC50=15nM against hSGLT2vs1.16nM for dapagliflozin。换言之,3-OH脱氧产物D3与受体SGLT2转运蛋白的亲和力较dapagliflozin有所减弱,进而导致SGLT2耦合葡萄糖的能力略微降低,说明3-OH对于SARs而言在一定程度上是不可或缺的。但就其是否具备成药能力而言,3-OH也不是不可或缺。因此,3-OH的存在究竟是利大于弊还是弊大于利还需要进一步药理数据的支撑。
2-OH脱氧产物的SGLT2抑制能力俨然己完全丧失。换言之,2-OH对于dapagliflozin与受体SGLT2转运蛋白的亲和力起着完全不可替代的作用。2-OH是先导化合物dapagliflozin维持生物活性的必需基团。
对四个单脱氧达格列净化合物生物活性研究SARs的结果激起了我进一步研究二脱氧达格列净的兴趣。基于对单脱氧产物生物活性数据的支撑,我优先选择合成最可能拥有降血糖活性的D36(3,6-deoxydapagliflozin)。
化合物D36的降血糖活性已经完全消失,IC50=3633nM against hSGLT2vs1.16nM for dapagliflozin。说明当dapagliflozin糖环片段的6-OH和3-OH同时被脱氧后,所得产物与受体SGLT2转运蛋白的亲和力完全丧失。换言之,dapagliflozin糖环片段的羟基数目必须保持在不少于三个,这样才能保持整个分子的极性以保证其与受体SGLT2转运蛋白的亲和力,以维持药物分子的SGLT2抑制能力。
本论文对dapagliflozin糖环片段的四个羟基进行系统的单脱氧和双脱氧研究促进了高效SGLT2抑制剂D6的出现。D6较先导化合物dapagliflozin拥有更加强大的SGLT2抑制活性；大鼠的口服葡萄糖耐量测试(OGTT)和尿糖排量测试(UGE)均表明它拥有更加强大的降血糖能力和增加尿糖排泄的能力。这个生物活性评价测试也说明6-OH的存在妨碍了dapagliflozin的SGLT2抑制能力,6-OH的脱氧反而增强了其SGLT2活性。尽管其选择性SGLT2/SGLT1(374)较dapagliflozin(SGLT2/SGLT1(823))选择性有所降低,但是这并不影响其成药性。
Diabetes mellitus is a metabolic disease about glucose, protein and adipose, which can lead to the rise of plasma glucose level. Due to the progressive essence of the disease, untreated hyperglycemia causes the damages of tissues which can result in many complications about micro-and macro-vascular lesions including retinopathy, nephropathy, and neuropathy, as well as stroke and coronary artery disease. It inhibits wound healing as well which accelerates infections and gangrene of lower limb. Long-term hyperglycemia induces oral health problems and sleep apnea. Persistent high plasma glucose levels speed up insulin resistance but also advance beta-cell apoptosis. With the development of living standard and changes of life-style, diabetes mellitus becomes more and more alarming worldwide.
Diabetes mellitus is mainly composed of two common forms including type2diabetes mellitus and type1diabetes mellitus. Type1diabetes mellitus also known as insulin-dependent diabetes mellitus (IDDM), is caused by the autoimmune breakdown of pancreatic β-cell, and thus bring about the reduction or vanishing of organismal insulin production. Type2diabetes mellitus also known as non-insulin-dependent diabetes mellitus (NIDDM), is featured by the loss of sensitive tissues to reply to insulin (insulin resistance) and by the beta-cell disfunction causing high concentration of blood sugar. T2DM accounts for90-95%among all the clinical diagnosis patients. What's more, these current antidiabetic drugs have side effects in different degree, such as weight gain, hypoglycemic, water retention and gastrointestinal side effects (naupathia and vomit). Traditional antidiabetic medications mostly focus on exploiting these drugs which boost endogenous insulin secretion and/or elevate insulin sensitivity. The progressive nature of diabetes determines single therapy and/or combination therapy unsatisfied with the whole process control of diabetes mellitus. Not all patients with DM can achieve targeted glycemic control levels (HbA1c□7.0%) according to the United Kingdom Prospective Diabetes Study (UKPDS). Thus well-tolerated novel drugs with patent mechanisms of action are required at every phase of the disease to regulate glucose level.
The kidney reabsorbs plasma glucose when it is filtered in the glomerulus. Thus, the kidney plays a very important role in glucose homeostasis. Hyperglycemia is the quality of T2MD. We can develop a kind of drug that has the ability to inhibit/stop the reabsorption of glucose to achieve the goal of lowering plasma glucose. This mechanism of action is other than traditional antidiabetic drugs above-mentioned.
As we know, glucose taked in human body largely is absorbed in small intestinal aided by SGLT1, and residual glucose is filtered in the glomerulus when it arrives in the kidney. The residue is reabsorbed in the proximal tubules (PT). The reabsorption process is mediated by two SGLTs, SGLT2and SGLT1included. More than90%glucose returns to the blood circle activated by SGLT2in S1segment of the PCT, and less than10%glucose aided by SGLT1. Therefore, we can design and synthesize novel compounds used for inhibiting the reabsorption of renal glucose to attain plasma glucose levels. And thus SGLT2inhibitors are becoming more and more attractive for chemists and pharmacologists.
This paper is based on the current situation about antidiabetics globally, analyzing the structures of SGLT2inhibitors marketed or under different clinical stages, and come to a conclusion that almost all SGLT2inhibitors chose dapagliflozin as lead-compound. Canagliflozin, ipragliflozin and empagliflozin were synthesized by modifications of aglycon in lead-compound dapagliflozin while holding the sugar moiety invariant. LX4211and PF-04971729were synthesized by modifications of moiety in dapagliflozin while holding aglycon invariant. The obtainments of tofogliflozin and TS-071rooted in the modifications of the lead compound dapagliflozin, the aglycon and the sugar moiety included. These modifications of dapagliflozin abided by the rules that polarity of sugar moieties and aromaticity and lipophilicity of aglycons. In other words, the appropriate polarity and aromaticity coming from SGLT2inhibitors can maintain biological activity.
The starting point of aforementioned three kinds of SGLT2inhibitors were designed and synthesized rooting in modifications of dapagliflozin. However, no one elaborated four hydroxyl groups of the sugar moiety on SARs.
This paper chose dapagliflozin as the lead compound and deoxidized four hydroxyl groups solely in turn and deoxidized four hydroxyl groups in couples respectively (see Fig.l). The products included D6(6-deoxydapagliflozin), D4(4-deoxydapagliflozin), D3(3-deoxydapagliflozin) and D2(2-deoxydapagliflozin). The in vitro assays of D6, D4, D3and D2against hSGLT2and hSGLTl were performed according to the reported procedure. The results of in vitro assays told us the structure-activity relationships (SRAs) of the four hydroxyl groups in the sugar moiety of dapagliflozin.
D6(6-deoxydapagliflozin) was found to be a significantly more active SGLT2inhibitor (IC50=0.67nM vs1.16nM), which demonstrated that6-OH is completely unnecessary for SGLT2inhibitory activity and the existence of6-OH lowers SGLT2 inhibitory in some degree.
D4(4-deoxydapagliflozin) was less active against hSGLT2by one order of magnitude than parent compound dapagliflozin (IC50=12.8nM vs1.16nM), indicating that4-OH is also vital to SGLT2inhibition.
D3(3-deoxydapagliflozin) exhibited a little bit lower hSGLT2inhibitory activity (IC50=1.5nM vs1.16nM) but slightly higher hSGLT2/hSGLTl selectivity (986vs823) as compared with dapagliflozin, which made D3basically comparable with dapagliflozin, indicating that3-OH is unnecessary for both SGLT2inhibition and hSGLT2/hSGLT1selectivity.
D2(2-deoxydapagliflozin) was almost completely inactive against hSGLT2(IC50=8,345nM), indicating that2-OH is indispensable for SGLT2inhibition.
The outcomes coming from the assays in vitro of D6, D4, D3and D2attracted the next di-deoxydapagliflozin derivatives. According to the aforementioned outcomes, we chose D36(3,6-dideoxydapagliflozin) as targeted molecular compound.
The assay of D36in vitro elaborated that3-OH and6-OH were deoxidized simultaneously, resulting in SGLT2inhibitory of the product vanishing completely. In other words, the deoxylations of6-OH and3-OH of the lead compound changed polarity and aromaticity completely. The affinity between acceptor (SGLT2) with D36(3,6-dideoxydapagliflozin) became very week so that the SGLT2ability of the D36(3,6-dideoxydapagliflozin) disappeared thoroughly. Only the numbers of hydroxyl groups in the sugar moiety of dapagliflozin not less than three could the SGLT2inhibitory be sustained.
Systematic mono-deoxylation and di-deoxylation of the four hydroxyl groups in the glucose moiety of the lead compound dapagliflozin lea to the discovery of D6as a more potent SGLT2inhibitor (IC50=0.67nM against hSGLT2vs1.16nM for dapagliflozin). It exhibited more effective blood glucose inhibitory activity in rat OGTT and could induce more urinary glucose in rat urinary glucose excretion (UGE) test than its parent compound dapagliflozin. This finding demonstrates that the6-OH in the moiety of dapagliflozin lowers the affinity between itself with the protein SGLT2. It could be a more potent SGLT2inhibitor without the6-OH group in the moiety of dapagliflozin. Thus6-deoxylation can be well tolerated; however,6-deoxylation can lead to a slight decrease in terms of SGLT2/SGLT1selectivity, which was still high enough in the field of druggability.
随着人们对糖尿病发病机制研究的深入而研发出适用于不同发展阶段的抗糖尿病药物,但这些药物并不能使所有的糖尿病患者达到血糖控制标准(HbA1。<7.0%)。此外,目前这些抗糖尿病药物均具有不同程度的副作用,如体重增加、低血糖、水潴留及胃肠道副作用(恶心、呕吐)等。传统的降低糖尿病患者血糖的药物大部分集中在能够提高内源性胰岛素的分泌和/或者是提高机体周围组织对胰岛素的敏感性。几乎所有的患者都在经历糖尿病造成的胰腺功能逐渐衰竭的各个阶段。因此,寻找具有新的作用机制、更加安全和更加有效的抗糖尿病药物刻不容缓。
肾脏作为以原尿形式存在的葡萄糖重吸收的器官,它对人体的葡萄糖的自稳平衡起着特别重要的作用。高血糖是糖尿病的表现形式,设计合成一种阻止葡萄糖重吸收的药物使葡萄糖在尿液中以糖尿的形式排出体外,这也是降低血糖的一种新的途径。
体内的葡萄糖大部分被小肠吸收,剩余的葡萄糖流经肾脏时被过滤到肾小球中形成原尿。当原尿流经肾小管时,位于肾近曲小管官腔上皮细胞的载体蛋白SGLTs,会耦合着钠离子和葡萄糖穿过细胞膜而重新回到到血液中。SGLTs主要包括SGLT1和SGLT2,位于肾近曲小管S1段的SGLT2耦合超过90%的葡萄糖穿过细胞膜重新回到血液循环；剩余不足10%的葡萄糖与SGLT1耦合重新回到血液循环。因此,抑制SGLT2的转运活性进而特异性地抑制葡萄糖在肾脏中的重吸收,以达到控制糖尿病患者的血糖水平。以肾脏为靶器官的抗糖尿病药物SGLT2抑制剂成为化学家和药物学家研究的热点。
本论文立足于全球范围内抗2型糖尿病药物研究现状,对已经上市和正处于各期临床阶段的SGLT2抑制剂分子结构进行剖析,发现当前的SGLT2抑制剂绝大部分以dapagliflozin为先导化合物进行结构修饰。Canagliflozin、ipragliflozin和empagliflozin以dapagliflozin为模板,保持糖环片段结构不变,改变糖苷的配基芳香环片段；LX4211和PF-04971729则保持糖苷配基二苯甲烷结构不变,对糖环片段做了细微的改动；tofogliflozin和TS-071则对糖环片段和糖苷配基均作出不同程度地改造,但却依然遵循糖环片段结构相似性和配基部分芳香性即保持亲脂性合适。
上述三大类SGLT2抑制剂设计的出发点都是围绕着dapagliflzin,做出糖苷配基或/和糖环部分的改变。迄今为止,还没有任何一个药物研发者阐述糖环片段的羟基对于药物构效关系所起的作用。
本论文选择dapagliflozin作为先导化合物,对其糖环片段的四个羟基进行逐渐单一脱氧和组合脱氧,进而明确羟基对药物构效关系的影响。通过对脱氧产物D6(6-deoxydapagliflozin)、D4(4-deoxydapagliflozin)、D3(3-deoxydapagliflozin)和D2(2-deoxydapagliflozin)的生物活性评价(体外活性评价和体内活性评价),明确了dapagliflozin糖环片段的四个羟基对药物构效关系的影响。
6-OH的存在反而降低了先导化合物dapagliflozin的生物活性,IC50=0.67nMagainst hSGLT2vs1.16nM for dapagliflozin。换言之,6-OH脱氧产物D6与受体SGLT2转运蛋白的结合力较dapagliflozin增强,进而导致SGLT2耦合葡萄糖的能力降低,减少了葡萄糖在肾脏的重吸收而增加了尿糖的排泄。
4-OH脱氧产物的SGLT2抑制活性几乎完全丧失,说明4-OH在先导化合物dapagliflozin与受体SGLT2转运蛋白的亲和力上起着无可取代的作用。
3-OH脱氧产物的SGLT2能力较dapagliflozin有所下降,IC50=15nM against hSGLT2vs1.16nM for dapagliflozin。换言之,3-OH脱氧产物D3与受体SGLT2转运蛋白的亲和力较dapagliflozin有所减弱,进而导致SGLT2耦合葡萄糖的能力略微降低,说明3-OH对于SARs而言在一定程度上是不可或缺的。但就其是否具备成药能力而言,3-OH也不是不可或缺。因此,3-OH的存在究竟是利大于弊还是弊大于利还需要进一步药理数据的支撑。
2-OH脱氧产物的SGLT2抑制能力俨然己完全丧失。换言之,2-OH对于dapagliflozin与受体SGLT2转运蛋白的亲和力起着完全不可替代的作用。2-OH是先导化合物dapagliflozin维持生物活性的必需基团。
对四个单脱氧达格列净化合物生物活性研究SARs的结果激起了我进一步研究二脱氧达格列净的兴趣。基于对单脱氧产物生物活性数据的支撑,我优先选择合成最可能拥有降血糖活性的D36(3,6-deoxydapagliflozin)。
化合物D36的降血糖活性已经完全消失,IC50=3633nM against hSGLT2vs1.16nM for dapagliflozin。说明当dapagliflozin糖环片段的6-OH和3-OH同时被脱氧后,所得产物与受体SGLT2转运蛋白的亲和力完全丧失。换言之,dapagliflozin糖环片段的羟基数目必须保持在不少于三个,这样才能保持整个分子的极性以保证其与受体SGLT2转运蛋白的亲和力,以维持药物分子的SGLT2抑制能力。
本论文对dapagliflozin糖环片段的四个羟基进行系统的单脱氧和双脱氧研究促进了高效SGLT2抑制剂D6的出现。D6较先导化合物dapagliflozin拥有更加强大的SGLT2抑制活性；大鼠的口服葡萄糖耐量测试(OGTT)和尿糖排量测试(UGE)均表明它拥有更加强大的降血糖能力和增加尿糖排泄的能力。这个生物活性评价测试也说明6-OH的存在妨碍了dapagliflozin的SGLT2抑制能力,6-OH的脱氧反而增强了其SGLT2活性。尽管其选择性SGLT2/SGLT1(374)较dapagliflozin(SGLT2/SGLT1(823))选择性有所降低,但是这并不影响其成药性。
Diabetes mellitus is a metabolic disease about glucose, protein and adipose, which can lead to the rise of plasma glucose level. Due to the progressive essence of the disease, untreated hyperglycemia causes the damages of tissues which can result in many complications about micro-and macro-vascular lesions including retinopathy, nephropathy, and neuropathy, as well as stroke and coronary artery disease. It inhibits wound healing as well which accelerates infections and gangrene of lower limb. Long-term hyperglycemia induces oral health problems and sleep apnea. Persistent high plasma glucose levels speed up insulin resistance but also advance beta-cell apoptosis. With the development of living standard and changes of life-style, diabetes mellitus becomes more and more alarming worldwide.
Diabetes mellitus is mainly composed of two common forms including type2diabetes mellitus and type1diabetes mellitus. Type1diabetes mellitus also known as insulin-dependent diabetes mellitus (IDDM), is caused by the autoimmune breakdown of pancreatic β-cell, and thus bring about the reduction or vanishing of organismal insulin production. Type2diabetes mellitus also known as non-insulin-dependent diabetes mellitus (NIDDM), is featured by the loss of sensitive tissues to reply to insulin (insulin resistance) and by the beta-cell disfunction causing high concentration of blood sugar. T2DM accounts for90-95%among all the clinical diagnosis patients. What's more, these current antidiabetic drugs have side effects in different degree, such as weight gain, hypoglycemic, water retention and gastrointestinal side effects (naupathia and vomit). Traditional antidiabetic medications mostly focus on exploiting these drugs which boost endogenous insulin secretion and/or elevate insulin sensitivity. The progressive nature of diabetes determines single therapy and/or combination therapy unsatisfied with the whole process control of diabetes mellitus. Not all patients with DM can achieve targeted glycemic control levels (HbA1c□7.0%) according to the United Kingdom Prospective Diabetes Study (UKPDS). Thus well-tolerated novel drugs with patent mechanisms of action are required at every phase of the disease to regulate glucose level.
The kidney reabsorbs plasma glucose when it is filtered in the glomerulus. Thus, the kidney plays a very important role in glucose homeostasis. Hyperglycemia is the quality of T2MD. We can develop a kind of drug that has the ability to inhibit/stop the reabsorption of glucose to achieve the goal of lowering plasma glucose. This mechanism of action is other than traditional antidiabetic drugs above-mentioned.
As we know, glucose taked in human body largely is absorbed in small intestinal aided by SGLT1, and residual glucose is filtered in the glomerulus when it arrives in the kidney. The residue is reabsorbed in the proximal tubules (PT). The reabsorption process is mediated by two SGLTs, SGLT2and SGLT1included. More than90%glucose returns to the blood circle activated by SGLT2in S1segment of the PCT, and less than10%glucose aided by SGLT1. Therefore, we can design and synthesize novel compounds used for inhibiting the reabsorption of renal glucose to attain plasma glucose levels. And thus SGLT2inhibitors are becoming more and more attractive for chemists and pharmacologists.
This paper is based on the current situation about antidiabetics globally, analyzing the structures of SGLT2inhibitors marketed or under different clinical stages, and come to a conclusion that almost all SGLT2inhibitors chose dapagliflozin as lead-compound. Canagliflozin, ipragliflozin and empagliflozin were synthesized by modifications of aglycon in lead-compound dapagliflozin while holding the sugar moiety invariant. LX4211and PF-04971729were synthesized by modifications of moiety in dapagliflozin while holding aglycon invariant. The obtainments of tofogliflozin and TS-071rooted in the modifications of the lead compound dapagliflozin, the aglycon and the sugar moiety included. These modifications of dapagliflozin abided by the rules that polarity of sugar moieties and aromaticity and lipophilicity of aglycons. In other words, the appropriate polarity and aromaticity coming from SGLT2inhibitors can maintain biological activity.
The starting point of aforementioned three kinds of SGLT2inhibitors were designed and synthesized rooting in modifications of dapagliflozin. However, no one elaborated four hydroxyl groups of the sugar moiety on SARs.
This paper chose dapagliflozin as the lead compound and deoxidized four hydroxyl groups solely in turn and deoxidized four hydroxyl groups in couples respectively (see Fig.l). The products included D6(6-deoxydapagliflozin), D4(4-deoxydapagliflozin), D3(3-deoxydapagliflozin) and D2(2-deoxydapagliflozin). The in vitro assays of D6, D4, D3and D2against hSGLT2and hSGLTl were performed according to the reported procedure. The results of in vitro assays told us the structure-activity relationships (SRAs) of the four hydroxyl groups in the sugar moiety of dapagliflozin.
D6(6-deoxydapagliflozin) was found to be a significantly more active SGLT2inhibitor (IC50=0.67nM vs1.16nM), which demonstrated that6-OH is completely unnecessary for SGLT2inhibitory activity and the existence of6-OH lowers SGLT2 inhibitory in some degree.
D4(4-deoxydapagliflozin) was less active against hSGLT2by one order of magnitude than parent compound dapagliflozin (IC50=12.8nM vs1.16nM), indicating that4-OH is also vital to SGLT2inhibition.
D3(3-deoxydapagliflozin) exhibited a little bit lower hSGLT2inhibitory activity (IC50=1.5nM vs1.16nM) but slightly higher hSGLT2/hSGLTl selectivity (986vs823) as compared with dapagliflozin, which made D3basically comparable with dapagliflozin, indicating that3-OH is unnecessary for both SGLT2inhibition and hSGLT2/hSGLT1selectivity.
D2(2-deoxydapagliflozin) was almost completely inactive against hSGLT2(IC50=8,345nM), indicating that2-OH is indispensable for SGLT2inhibition.
The outcomes coming from the assays in vitro of D6, D4, D3and D2attracted the next di-deoxydapagliflozin derivatives. According to the aforementioned outcomes, we chose D36(3,6-dideoxydapagliflozin) as targeted molecular compound.
The assay of D36in vitro elaborated that3-OH and6-OH were deoxidized simultaneously, resulting in SGLT2inhibitory of the product vanishing completely. In other words, the deoxylations of6-OH and3-OH of the lead compound changed polarity and aromaticity completely. The affinity between acceptor (SGLT2) with D36(3,6-dideoxydapagliflozin) became very week so that the SGLT2ability of the D36(3,6-dideoxydapagliflozin) disappeared thoroughly. Only the numbers of hydroxyl groups in the sugar moiety of dapagliflozin not less than three could the SGLT2inhibitory be sustained.
Systematic mono-deoxylation and di-deoxylation of the four hydroxyl groups in the glucose moiety of the lead compound dapagliflozin lea to the discovery of D6as a more potent SGLT2inhibitor (IC50=0.67nM against hSGLT2vs1.16nM for dapagliflozin). It exhibited more effective blood glucose inhibitory activity in rat OGTT and could induce more urinary glucose in rat urinary glucose excretion (UGE) test than its parent compound dapagliflozin. This finding demonstrates that the6-OH in the moiety of dapagliflozin lowers the affinity between itself with the protein SGLT2. It could be a more potent SGLT2inhibitor without the6-OH group in the moiety of dapagliflozin. Thus6-deoxylation can be well tolerated; however,6-deoxylation can lead to a slight decrease in terms of SGLT2/SGLT1selectivity, which was still high enough in the field of druggability.
引文
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