2型糖尿病治疗新靶点SGLT2抑制剂的研究进展_徐鸽
现代生物医学进展https://www.360docs.net/doc/cd18218571.html, Progress in Modern Biomedicine 2009Vol.9No.132型糖尿病治疗新靶点SGLT2抑制剂的研究进展
徐鸽1沈玫1吕彬华2许百华2李绍顺1△
(1上海交通大学药学院上海200240;2白鹭医药技术(上海)有限公司上海201203)
摘要:钠-葡萄糖协同转运蛋白(SGLT )是一类在小肠粘膜(SGLT1)和肾近曲小管(SGLT2和SGLT1)中发现的葡萄糖转运基因家族。它们用于肾脏血糖的重吸收。SGLT2是一种低亲和力的转运系统,其在肾脏中特异性的表达并且在近曲小管的肾脏血糖重吸收中发挥非常重要的作用。选择性地抑制SGLT2,是一种创造性的治疗策略,即通过增加尿糖的排出来治疗2型糖尿病患者。本文介绍了SGLT2抑制剂在2型糖尿病治疗研究方面的最新进展,重点综述了SGLT2抑制剂的作用机理、部分在研SGLT2抑制剂的生物活性数据以及临床试验结果。
关键词:2型糖尿病;药物治疗;钠-葡萄糖协同转运蛋白;抑制剂中图分类号:
R587.1,R914文献标识码:A 文章编号:1673-6273(2009)
13-2569-04Progress in Sodium-glucose Co-transporter-2Inhibitors:the New
Target for Treatment of Type 2Diabetes
XU Ge 1,SHEN Mei 1,LV Bin-hua 2,XU Bai-hua 2,LI Shao-shun 1△
(1School of Pharmacy,Shanghai Jiao Tong University,Shanghai 200240,China;
2Egret Pharma (Shanghai)Limited,Shanghai 201213,China )
ABSTRACT:Sodium-glucose co-transporters (SGLT)are a family of glucose transporter found in the intestinal mucosa of the small intestine (SGLT )and the proximal tubule of the nephron (SGLT2and SGLT1).They contribute to renal glucose reabsorption.The sodi-um-glucose co-transporter-2(SGLT2)is a low-affinity transport system that is specifically expressed in the kidney and play a very impor-tant role in renal glucose reabsorption in the proximal tubule.Selective inhibition of SGLT2is an innovative therapeutic strategy for treat-ment of type 2diabetes patients by enhancing glucose loss through the urine.In this paper,the latest research progress on SGLT2inhi-bitors for the treatment of type 2diabetes were introduced.We emphasized the mechanism of SGLT2inhibitors,the data of biological ac-tivities and clinical trials of some SGLT2inhibitors under research and development.
Key words:Type 2diabetes;Drug therapy;Sodium-glucose co-transporters (SGLT);Inhibitors Chinese Library Classification:R587.1,R914Document code:A Article ID:1673-6273(2009)
13-2569-04作者简介:徐鸽(1981-),男,硕士研究生,主要研究方向:抗2型糖尿病新药研究和开发,电话:
021-********-8302,E-mail:xuge@https://www.360docs.net/doc/cd18218571.html, △通讯作者:李绍顺,E-mail:ssli@https://www.360docs.net/doc/cd18218571.html, (收稿日期:2009-05-03接受日期:2009-06-01)
前言
糖尿病主要分为1型糖尿病和2型糖尿病,前者是由于胰岛β-细胞不能产生足够的胰岛素(胰岛素绝对缺乏)所致[1],后者是由于胰岛素分泌不足或胰岛素抵抗(胰岛素相对缺乏)所致[2]。糖尿病患者中约有90~95%属于2型糖尿病。据2009年5月18日出版的《中国医药报》报道,全球已确诊的糖尿病患者总数高达2.47亿人,且高血糖人数仍在不断上升,糖尿病药物市场已经成为一个高速增长的大市场,对于降糖新药的开发研究早已成为国际药学界的热门课题。2008年全球糖尿病药物市场总销售额高达240亿美元。在排名前10位的降糖类药物中,两个上市已达10年的噻唑烷二酮类降糖药物仍稳居全球糖尿病药物市场前5位:
由日本武田化学株式会社(Takeda 药业)开发生产的吡格列酮制剂Actos ,2008年销售额高达42亿美元,排名第一;由葛兰素史克公司研制并生产的罗格列酮制
剂(文迪雅),去年销售额达16亿美元,排名第五。2007年9月出版的美国医学协会期刊(JAMA )刊登的论文比较了糖尿病药物文迪雅和Actos 的副作用风险。很多数据表明,文迪雅有显著增加心肌梗塞的风险。相比而言,Actos 能够降低心脏病、脑卒中和死亡风险达18%。
但是,这两种药物均增加心衰的风险,这种副作用已经标注在药品说明上。如Actos 增加心衰的风险达41%[3,4]。因此,为越来越多的糖尿病患者提供更加有效且毒副作用小的治疗药物,已成为学术界、医药学界、工业界共同关注和期待解决的重大课题。
尽管目前口服糖尿病药物作用机制多种多样,但是临床上还没有一种药物是基于通过控制身体能量摄入和能量消耗的“能量平衡”达到治疗糖尿病的目的[5]。体内贮存的能量不仅能被肠和肌肉消耗掉,而且可以在肾里通过尿排出多余的糖。因此,采用类似运动或生活方式调节体内能量平衡的策略是可行的。如果有药物能够刺激尿糖的排出从而影响“能量平衡”,使平衡朝着能量消耗的方向移动,从而达到降低体内血糖的目的,极有可能给2型糖尿病患者提供一种新的药物治疗手段。
在肾小管里,钠-葡萄糖协同转运蛋白2(sodium-glucose co-transporter-2,SGLT2)在葡萄糖的重吸收中起主要的作用:SGLT2转运肾重吸收葡萄糖的90%,而SGLT1只占其余的
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10%[6]。因此抑制SGLT2活性,从而特异性地抑制肾脏对葡萄糖的重吸收,是寻找潜在抗糖尿病药的新靶点。
1钠-葡萄糖协同转运蛋白
在生物体内,葡萄糖无法自由通过细胞膜的脂质双层结构,必须借助于细胞膜上的葡萄糖转运蛋白,因此,葡萄糖转运蛋白是调控细胞糖代谢的第一道关卡。研究表明,肾脏中存在两大类葡萄糖转运蛋白
[7,8]
,一类是钠依赖的葡萄糖转运蛋白
(sodium-dependent glucose transporters ,
SGLTs )或SLC5基因家族[9];另一类是易化扩散的葡萄糖转运蛋白(glucose trans-
porter ,GLUT )或SLC2基因家族[10]。SGLT 以主动方式逆浓度梯度转运葡萄糖,同时消耗能量,而GLUT 以易化扩散方式顺
浓度梯度转运葡萄糖,其转运过程不消耗能量。SGLT 主要分布于肾小管上皮细胞管腔侧,小管液中葡萄糖通过SGLT 进入细胞后,又能被上皮细胞基底膜侧的GLUT 转运至周围毛细血管网中,从而完成肾小管对葡萄糖的重吸收。钠依赖的葡萄糖转运蛋白(SGLTs )对维持人体血糖稳定起着关键作用。SGLTs 已在肠(SGLT1)和肾(SGLT1和SGLT2)中发现。肾SGLT 从肾滤过液中再吸收葡萄糖,从而防止血糖从尿中丢失。
2SLC5基因家族的功能和体内分布
到目前为止,钠-葡萄糖协同转运蛋白(SLC5A )共有12个成员,其中包含6个命名为SGLTs 蛋白[11]
。在人体内的
SGLTs 及其组织分布(见表1)。
Note:1,5-AG 1,5-anhydro-D-glucitol,CHT choline transporter,NIS Na+/iodide transporter,SMCT sodium-dependent monocarboxylate transporter,SMIT sodium-dependent Myo-inositol transporters,SMVT sodium-dependent multivitamin transporter.*Glucose is not a substrate but an agonist for SLC5A4working as a sensor.
Gene Protein Substrates Tissue distribution
SLC5A1SGLT1Glucose and galactose
Small intestine,heart,trachea and kidney
SLC5A2SGLT2Glucose Kidney
SLC5A3SMIT Myo-inositol Thyroid gland,testis,kidney,lung and trachea SLC5A4SGLT3Glucose sensor*
Small intestine,uterus,lung,thyroid gland and
testis
SLC5A5NIS Iodide
Thyroid gland,salivary gland and stomach SLC5A6SMVT Pantothenate,biotin and lipoate
Placenta,testis,skeletal muscle,liver and small
intestine SLC5A7CHT Choline
Spinal cord
SLC5A8SMCT1Short-chain fatty acids,lactate and nicotinate Thyroid gland,trachea,kidney and prostate SLC5A9SGLT4Mannose,glucose,fructose,1,5-AG and
galactose Small intestine,kidney,liver,stomach and lung
SLC5A10SGLT5Glucose and galactose
Kidney
SLC5A11SGLT6Myo-inositol,glucose,xylose and chiro-inositol Spinal cord,kidney,brain and small intestine
SLC5A12
SMCT2
Short-chain fatty acids,lactate and nicotinate
Kidney and small intestine
表1人体SLC5A 基因家族及其组织分布
Table 1Tissue distribution of SLC5A gene family in humans
SGLT1(SLC5A1)以钠-葡萄糖2:1的比率转运D-葡萄糖和D-半乳糖,主要分布在肠[12]。SGLT2(SLC5A2)以钠-葡萄糖1:1的比率转运D-葡萄糖(见图1),主要分布在最接近肾的顶端小管里[13,14]。其59%基因序列和SGLT1相同[13,15]。由于SGLT2缺陷的病人有大量尿糖排出[16],表明SGLT2主要参与了肾葡萄糖重吸收。SGLT3(SLC5A4)不转运葡萄糖,但是在类胆碱神经元细胞膜中发挥传感器作用[17]。SGLT4(SLC5A9)不仅转运葡萄糖,而且转运D-甘露糖、
1,5-脱氢-D-葡萄糖醇(1,5-AG
)和D-果糖[18],此与先前假定的D-甘露糖/1,5-脱氢-D-葡萄糖醇(1,5-AG )
/D-果糖转运体一致[19]
。人体SGLT5
(SLC5A10)转运D-葡萄糖和D-半乳糖,和SGLT2类似,分布在肾小管和肾小球的上皮组织中[20]。SGLT6(SLC5A11)转运对渗透平衡重要的肌糖、葡萄糖和木糖[21]。其它的SLC5A 蛋白质,
SLC5A3[22],SLC5A5[23],SLC5A6[24],SLC5A7[25],SLC5A8[26]和SLC5A12[27]均不转运糖。
Note:SGLT1主要表达于小肠刷状缘和肾近曲小管较远的
S3节段中,少量表达于心脏和气管,SGLT2则主要表达于肾近曲小管前S1节段中。SGLT1负责转运葡萄糖和半乳糖,而SGLT2则只负责转运葡萄糖。对于高亲和力的SGLT1,Na+对转运的葡萄糖的摩尔比为2:1,而对于低亲和力的SGLT2,其摩尔比为1:1。
图1SGLT2和SGLT1的在肾中的分布及转运葡萄糖的方式[14]Figure 1The distribution of SGLT2and SGLT1in the kidney and their
transport manner of
glucose
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Note:在肾脏,葡萄糖可以自由地从肾小球滤过,但是基本在近曲小管主动转运而重吸收。SGLT2在葡萄糖的重吸收中起主要的作用,它转运肾重吸收葡萄糖的90%,而SGLT1转运其余的10%。所以,
SGLT2的抑制剂可以阻断近曲小管对葡萄糖的重吸收而通过尿排出多余的糖。
4研发中的SGLT2抑制剂
近几年,越来越多的研究者以SGLT2作为分子靶点,寻找特异性SGLT2抑制剂使体内多余的糖直接以尿糖排出,从而使2型糖尿病患者血糖恢复正常。第一个被评价的SGLT 抑制剂是从苹果树的根皮中分离出来的根皮苷(Phlorizin ,
结构见图3)[28]
。虽然Phlorizin 通过增加肾中尿糖的排出,表现出抗糖尿
病活性、降低血糖和改善胰岛素抵抗,但是由于其在小肠中容易被根皮苷水解酶水解导致生物利用度低[28],最终Phlorizin 没有被发展成抗糖尿病药物。随后,
Tanabe Seiyaku 和John-son&Johnson 公司开发了第一个口服吸收的SGLT2抑制剂T-1095(结构见图3),它是Phlorizin 的类似物,但克服了Phlo-rizin 的一些缺点。作为一个甲基碳酸酯前药,口服后T-1095在小肠里很快就转化为活性体T-1095A 。而T-1095A 是SGLT1和SGLT2的双抑制剂[29],在体外,对人体SGLT2和SGLT1的IC 50分别为50nM 和200nM ,选择性不高[29,30]。Kissei 制药公司和GlaxoSmithKline 公司开发的选择性SGLT2抑制剂Ser-gliflozin (GW-869682,结构见图3)正处于临床II 期研究。在体外,对人体的SGLT2的IC 50为350nM ,该化合物为乙基碳酸酯前药,在体内转化为Sergliflozin-A ;另外该化合物还被Glaxo-SmithKline 公司作为潜在的治疗肥胖药物处于临床II 期试验。Kissei 制药公司和GlaxoSmithKline 公司另外一个SGLT2抑制剂Remogliflozin
(GW-189075,结构见图3)也处于临床II 期研究,在体外,对人体的SGLT2的IC 50为30±5nM ,其选择性(SGLT2>SGLT1)为60。该化合物在SD 大鼠里,口服生物利用度是27%,口服用量10mg/kg ,尿糖排出率为167.3mg/24
h/200g 体重
[31]
。当然,目前该领域的领先者是Bristol-Myers
Squibb 和AstraZeneca 公司开发的Dapagliflozin (BMS-512148,结构见图3),目前处于临床III 期研究。在体外,对人的SGLT2和SGLT1的EC50分别为1.1±0.06nM 和1390±7nM ,选择性(hSGLT2>hSGLT1)为1200倍,远远高于Phlorizin 的10倍选择性。对老鼠的SGLT2和SGLT1的EC50是3nM 和600nM ,选择性(rSGLT2>rSGLT1)减少为200倍。大鼠口服0.1、1.0、10mg/kg 的Dapagliflozin ,尿糖的排出率分别为550、1100、1900mg/24h/200g 体重[32]。
4.1部分在研SGLT2抑制剂的化合物结构(图3)
4.2目前公布的SGLT2抑制剂的临床数据(表3)
[6]
5展望
综上所述,
SGLT2抑制剂能够刺激尿糖的排出从而影响“能量平衡”,使平衡朝着能量消耗的方向移动,从而达到降低体内血糖的目的。而最近公布的临床数据也证实,SGLT2抑制剂对于治疗糖尿病尤其是2型糖尿病有非常好的疗效。
目前,全球许多医药公司和研发机构正在不断加大投入,积极开发SGLT2抑制剂作为治疗2型糖尿病的新药物。相信在不久的将来,会有越来越多的新的SGLT2抑制剂进入临床研究阶段。所以,能够抑制SGLT 特别是SGLT2的化合物是很有前景的候选抗2型糖尿病药物
。
图2SGLT2抑制剂的作用机理Figure 2Mechanism of SGLT2inhibitors
Dose (mg/kg)1C max (PO dose,μg/mL)
0.6T max (PO dose,h)
1.7T 1/2(h) 4.6F (%)84V ss (L/Kg) 1.6Cl (mL/min/kg)
4.8
表2Dapagliflozin 在大鼠中的药代动力学数据[32]Table 2Pharmacokinetic profile of Dapagliflozin in
Rats
图3A)Phlorizin;B)T-1095;C)Sergliflozin;D)Remogliflozin;E)
Dapagliflozin
Figure 3A)Phlorizin;B)T-1095;C)Sergliflozin;D)Remogliflozin;E)
Dapagliflozin
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Table3Summary of published clinical trials
(上接第2572页)
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启动子;caspase9则是线粒体介导的凋亡途径中的关键启动子。
3结语
细胞凋亡对肿瘤的发生、发展有着十分重要的作用。TGF-β是机体正常细胞及肿瘤细胞生长的负调节因子,它在肿瘤细胞的凋亡及肿瘤的发生发展中都有着不可替代的作用。而作为凋亡机制中重要的效应子成分,Caspase家族参与多种与凋亡有关的生理和病理过程。通过进一步研究两者生物功能,从细胞凋亡角度来理解和研究肿瘤的发生、发展机制,重建肿瘤细胞的凋亡信号传递系统,激活凋亡相关基因的表达,对肿瘤的治疗方法将具有重要的理论和临床意义。
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