CN101594886A - 偶合到用于成像表达肽酶的组织和器官的肽酶结合部分的放射影像部分 - Google Patents
偶合到用于成像表达肽酶的组织和器官的肽酶结合部分的放射影像部分 Download PDFInfo
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- CN101594886A CN101594886A CNA2007800403852A CN200780040385A CN101594886A CN 101594886 A CN101594886 A CN 101594886A CN A2007800403852 A CNA2007800403852 A CN A2007800403852A CN 200780040385 A CN200780040385 A CN 200780040385A CN 101594886 A CN101594886 A CN 101594886A
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Abstract
本发明公开的偶联物、方法和试剂盒用于成像表达一种或多种肽酶的组织和器官。在本发明的优选实施例中,一系列二-(2-吡啶甲基)胺(D)配位体,其和M(CO)3 +[M=Tc或Re]结合,并和赖诺普利(L)偶合。利用不同亚甲基基团(3、4、5和7;D(C4)L、D(C5)L、D(C6)L和D(C8)L,分别的)数目的脂肪链,随着亚甲基数目的增加,体外抑制活性也增加。观察到D(C8)L偶联物比D(C4)L的功效显著。在组织分布和射线成像研究中研究了ACE的体内特异性,证实有高ACE含量在组织中定位。定位通过赖诺普利的预治疗阻断。
Description
相关申请的交叉应用
本申请要求2006年8月29日提交的美国临时申请60/823,884的优先权,该临时申请公开的全部内容通过引用全部结合到申请中。
感谢
本项工作得到了全国健康协会(NIH)的拨款支持,即健康和人类服务部门,1-R43-HL075918-01。联邦政府对本发明有一定的权利。
引言
许多组织(包括血液)和器官表达不同水平的肽酶(也称为蛋白酶、朊酶和蛋白水解酶)。表达水平根据和组织或器官相关的病理学条件(或缺失病理学条件)也可能不同。例如,已经知道,在心力衰竭受害者的心肌中发现了高水平的血管紧张肽转化酶(ACE)。
MEROPS数据库(http://merops.sanger. )是肽酶及抑制肽酶的蛋白质的信息源。MEROPS数据库也含有所选择肽酶的小分子抑制剂的清单。参考:Rawlings,N.D.,Morton,F.R.&Barrett,A.J.(2006)MEROPS:the peptidase database.Nucleic Acids Res34,D270-D272。该数据库的内容,特别是7.5版,通过应用结合到本发明的说明书中。
作为肽酶的抑制剂,这些分子(无论是大分了如蛋白质,或小分子,包括肽酶和现有的药物或或候选药物)也结合到肽酶上,它们抑制一定的亲和力。
ACE:示例的肽酶
尽管降低死亡率的趋势归因于缺血性心脏病和中风,但是,在美国,充血性心力衰竭的流行和由此导致的死亡率在过去三十年几乎超过了三倍。参考S.Y.Chai,F.A.O.Mendelsohn,G.Paxinos,Neuroscience,20:615-627(1987)。据估计,在接下来的二十年,由于冠心病导致的心力衰竭将超过所有的传染病,从而变成世界上造成死亡的主要原因。参考M.R.Cowie,D.A.Wood,A.J.S Coats,S.G.Thompson,P.A.Poole-Wilson,V.Suresh,G.C.Sutton,Eur.Heart J.,20:421-428(1999)。
因此,需要更新和更好的方法来诊断、治疗和监测某些疾病的进展,如心力衰竭。
赖诺普利,一个示例的肽酶结合部分
赖诺普利,一种临床应用的ACE抑制剂,用于治疗充血性心力衰竭和高血压,已经显示能够直接对ACE抑制。根据充血性心力衰竭患者的心脏切片的初步放射自显影的结果,参考V.Dilsizian,J.Shirani,Y.H-C.Lee,D.Kiesewetter,E.M.Jagoda,M.L.Loredo,W.C.Eckelman,Circulation,104:17,3276(2001),发明人确信ACE可能是有吸引力的、用于心力衰竭的诊断、确定和治疗的分子靶。类似的,发明人相信,在某些组织和器官中,其它肽酶的过表达可以开发用于诊断、治疗和监测多种病理症状的进展。这些病理症状包括但不限于心力衰竭、心肌症、肺病、肾功能不全、肾衰竭、炎症、动脉硬化、易损动脉斑块或肿瘤,如乳腺癌、前列腺癌、胃癌、肝细胞癌、肺癌,等等。其它的病理症状包括心脏血管疾病,通常包括糖尿病肾病、过量组织ACE活性、非胰岛素依赖糖尿病或高血压导致的慢性肾病、高血压外围血管疾病、肺气肿(或慢性阻塞型肺气肿-COPD),等等。
发明内容
本发明涉及一系列的偶联物,该偶联物将肽酶结合部分(如抑制肽酶的物质)和放射性药物部分(包括放射性治疗和声像部分)或光学影像部分合并。肽酶包括但不限于外肽酶(如羧肽酶和氨肽酶)和内肽酶(如丝氨酸肽酶、半胱氨酸肽酶、天冬氨酸肽酶和金属内切肽酶)。“部分”是能够独立于另一部分存在的分子。因此,单独的取代基(如官能团),如羟基、卤素,等等,在本发明中不是“部分”。
在本发明的具体实施方案中,公开了一系列的偶联物,该偶联物基于金属螯合物和赖诺普利(二肽羧肽酶的抑制剂,a.k.a.血管紧张肽转化酶)的偶联。因此,对一系列基于赖诺普利的配位体(下面将进一步叙述)进行了合成和评价,能够结合金属物质(如M(CO)3 +[M=Tc或Re,特别是非放射性和放射性同位素])。合适配位体的实例包括但不限于二-(2-吡啶甲撑基)胺、二-(2-喹啉甲撑基)胺、二-(2-异喹啉)胺及类似物,这些配位体通过脂肪系链配位到赖诺普利或其它肽酶结合部分。体外试验分析证实,增加脂肪系链中的甲撑基的数目,导致抑制剂效能的增加。在存在或不存在赖诺普利的情况下,用正常的鼠研究了针对ACE的体内试验。这些体内试验研究证实组织内放射指示剂和高含量的ACE一起定位,所述定位用赖诺普利预处理阻断。
在本发明的另一实施方案中,公开了系列新型的99mTc-标记的ACE抑制剂的制备。这些偶联物具有监测体内ACE表达的能力,可以用于心血管疾病的分级,特别是充血性心力衰竭的分级。令人惊讶的,该系列中最有效的化合物,99mTc-D(C8)L,是能忍受最长链的化合物。该偶联物在ACE过表达的动物模型中评价,目的是评价其针对和分级心力衰竭(如通过定量ACE在心肌中的表达)的能力。相应的,表达ACE的组织或器官的成像方法是本发明的一个应用。在ACE表达的一个具体实例中,公开了一种成像肺组织、肾组织、心肌组织、肿瘤组织或这些组织的结合的方法。
本发明也涉及偶联到肽酶结合部分的光学成像部分(如荧光、化学发光或磷光),例如,非放射性(及“冷却的”)铼螯合物以二-(2-喹啉甲撑基)胺或二-(2-异喹啉)胺作为螯合配位体,连接到肽酶结合部分。光学成像的应用实例在Wei L,Babich JW,OuelletteW,Zubieta J.,Developing the{M(CO)3}+core for fluorescenceapplications:Rhenium tricarbonyl core complexes withbenzimidazole,quinoline,and tryptophan derivatives.InorgChem.2006 Apr 3;45(7):3057-66和James S,Maresca KP,BabichJW,Valliant JF,Doering L,Zubieta J.,Isostructural Re and99mTc complexes of biotin derivatives for fluorescence andradioimaging studies.Bioconjug Chem.2006May-Jun;17(3):590-6中进行了公开。本发明也包括将放射性治疗部分作为肽酶结合部分的偶联剂。术语“放射性治疗部分”意指包括放射影像部分、放射治疗部分或二者。放射治疗部分的实例可能是铼-186或铼-188三(羰基)二-(2-吡啶甲撑基)胺螯合物。
附图说明
图1显示了偶联到赖诺普利(L)的二-(2-吡啶甲撑基)胺(D)螯合物制备的合成路线。
图2显示的是赖诺普利和D(Cx)L化合物在体内生化试验中的剂量曲线。
图3显示的是99mTc-D(C5)L在正常和赖诺普利预处理(1mg/kg,i.v.)15分钟的Sprague Dawley鼠中的组织分布。
图4显示的是Sprague Dawley鼠中99mTc-D(C5)L的放射成像(左侧:没有用赖诺普利预处理;右侧:用赖诺普利预处理)。
图5显示的是配位体和相应的配位体金属络合物。配位体和配位体金属络合物可以和肽序列的C-端或N-端连接。
图6显示的是连接到氨基官能度的配位体和相应的配位体金属络合物。
图7显示的是连接到羧基官能度的配位体和相应的配位体金属络合物。
图8显示的是本发明化合物包括螯合步骤的合成路线图。
图9为对照(A)和99mTc(CO)3D(C8)L(MIP-1037)注射10分钟后赖诺普利预处理的(B)的体内分布所示的整体平面图的正视图。
图10显示的是小动物SPECT/CT图,该图显示的是对照鼠(A)注射99mTc(CO)3D(C8)L(MIP-1037)后肺的活性,其中在赖诺普利预处理的(B)中没有出现。
图11显示的是条形图中表II的结果。
具体实施方式
在本发明的优选实施例中,制备了成像ACE表达的探针。赖诺普利(“L”),ACE的抑制剂,用作起始药理学基序。二-(2-吡啶甲基)胺(“D”),能够结合M(CO)3 +[M=Tc或Re]的配位体,通过在赖诺普利赖氨酸残基的ε-胺处形成的酰胺键和赖诺普利结合。配位体包含有脂肪链,该脂肪链含有不同数目的次甲基间隔断基团(3、4、5和7;分别指定的D(C4)L、D(C5)L、D(C6)L和D(C8)L)。参考图1。
ACE抑制对照使用比色测定的鼠肺ACE在体外评价。用正常的雄性Sprague Dawley鼠在注射后15、60和120分钟、通过研究存在(n=6/时点)或不存在(n=4/时点)赖诺普利(1mg/kg i.v.)的组织分布和间隔对ACE的体内特异性进行99mTc-D(C5)L测定。
实施例
说明书中引用的文献的全部内容通过引用结合到本申请中。
偶联物的制备
从LKT实验室(Saint Paul,MN)中获得赖诺普利。根据文献中公开的方法,进行细微的变化,合成所有的配位体。参考M.K.Levadala,S.R.Banerjee,K.P.Maresca,J.W.Babich,J.Zubieta,Synthesis,11:1759-1766(2004);L.Wei,J.Babich,W.C.Eckelman,J.Zubieta,Inorg.Chem.,44:2198-2209(2005)。用HT实验室(San Diego,CA)的电喷雾质谱和DesertAnalytics(Tucson,AZ)进行元素分析。
D(C4)L(1):产量=40%(0.68g)。1H NMR(CDCl3,ppm):8.50(m,2H),7.62(m 2H),7.43(m,2H),7.13(m,8H),3.85(m,4H),3.69-2.60(mm,11H),2.26-1.41(mm,16H)。MS(ESI):m/z 674(M+1),m/z 672(M--1)。分析计算的C37H48N6O6·1.5H2O:C,63.50;H,7.35;N,12.01;O,17.15。实测:C,63.44;H,7.11;N,12.24,O,17.17.(MIP-1039)
D(C5)L(2):产量=34%(0.61g).1H NMR(CDCl3,ppm):8.51(m,2H),7.65(m 2H),7.51(m,2H),7.13(m,8H),3.92(d,4H),3.69-2.65(mm,11H),2.27-1.46(mm,18H).MS(ESI):m/z 688(M++1),m/z 686(M--1).分析计算:C38H50N6O6·H2O:C,64.75;H,7.44;N,11.92;O,15.89。实测:C,64.77;H,7.35;N,11.92;O,16.07.(MIP-1003)。
D(C6)L(3):产量=13%(0.23g).1H NMR(CDCl3,ppm):8.50(m,2H),7.64(m 2H),7.49(m,2H),7.15(m,8H),3.86(d,4H),3.68-2.60(mm,11H),2.26-1.41(mm,20H).MS(ESI):m/z 702(M++1),m/z 700(M--1).分析计算:C39H52N6O6·2.5H2O:C,62.80;H,7.70;N,11.27;O,18.23。实测:C,62.82;H,7.47;N,11.40;O,17.91。
D(C8)L(4):产量=35%(0.57g).1H NMR(CDCl3,ppm):8.50(d,2H),7.63(m 2H),7.50(m,2H),7.13(m,8H),3.85(d,4H),3.69-2.53(mm,11H),2.23-1.22(mm,24H).MS(ESI):m/z 730(M++1),m/z 728(M--1).分析计算:C41H56N6O6·H2O:C,65.93;H,7.83;N,11.25;O,14.99。实测:C,65.64;H,8.21;N,11.20;O,14.48.(MIP-1037)。
体外分析
根据生产者的说明(Fujirebio),用商业上获得的体外生物试验对每个化合物的浓度范围抑制p-羟基苯甲酰-甘氨酸L-组氨酰基-L-亮氨酸的ACE分裂的能力进行了检测。选择用于分析的ACE酶源为提纯的鼠肺ACE(Sigma),3.3mU/样品。赖诺普利在每个试验中作为阳性对照。图2显示的是这种分析产生的数据实例。用鼠肺ACE、赖诺普利、D(C4)L、D(C5)L、D(C6)L和D(C8)L分别得到2.5nM、83.3nM和42.8nM、42.5nM和19.5nM的IC50值。IC50值证实,尽管D(C8)L(组织:19.5nM)不是和赖诺普利(组织:2.5nM)一样有功效,但是和D(C4)L(组织:83.3nM)相比,则更有功效。总之,体外分析证实:随着联吡啶和核赖诺普利部分之间次甲基数目的增加,活性也在增加。
类似的,可以评价基于偶联到给定肽酶小分子抑制剂的螯合部分的偶联能力。表1列出了实例的肽酶数目及其基质。表2列出了所选择的肽酶的小分子抑制剂的示例数目。参考Moskowitz,D.W.Diabetes Technology&Therapeutics(2002)4(4):519-532,其中进一步讨论了特定疾病状态及和ACE相关的小分子抑制剂。
体内分析
正常雄性Sprague Dawley鼠分组进行了99mTc-D(C5)L组织分布和间隔的定量分析。在接受测试化合物之前,动物接受1mg/kg的赖诺普利5分钟,从而阻断靶器官的具体吸收,由此证实假设的体内作用机理。在所有测试的组织中检测99mTc-D(C5)L,其在整个试验过程中稳步减少。在肺中观察到吸收在注射15分钟后接近0.75±0.14%ID/g(图3)。99mTc-D(C5)L通过肾、肝和肠中化合物的水平证实了肾和肝胆二者的间隔。在注射放射标记的化合物之前,用1mg/kg的赖诺普利预处理5分钟,降低了肺中化合物吸收和保留(0.11±0.02%ID/g),这表示99mTc-D(C5)L特别结合体内ACE。
对于成像研究,将动物放置在γ照相机上,得到由5个1分钟连续图像组成的基线平面正视图。当在肠胃道和肝脏中检测到一个化合物的强信号,99mTc-D(C5)L显示了肺吸收,该吸收被赖诺普利(图4)预处理阻断,证实了组织分布研究中的检测结果。
ACE比色测定试验报告
根据生产者的说明书,血管紧张素转换酶(ACE)的活性用ACE彩色套件(Fujirebio)进行测定。ACE作用于p-羟基苯甲酰-甘氨酸L-组氨酰基-L-亮氨酸,产生p-羟基苯甲酰-甘氨酸,其通过马尿酸酶转化成p-羟基苯甲酸。p-羟基苯甲酸和氨基安替比林通过偏高碘酸钠氧化和浓缩生成醌亚胺染料。醌亚胺染料的浓缩通过其在505nm处的最大吸收进行定量测定。在ACE比色测定中,该试验用于比较铼标记的ACE抑制剂的组织和血浆特异性。
鼠血清的制备:不用抗凝剂,用注射器和16-规针心脏穿刺从正常鼠取血,并将其输送到15ml的圆锥管中。该管用冰冷却30分钟,使血凝结。除去凝结的血,剩下的血清在室温、5,000Xg分离10分钟。回收上清液,用0.22微米的过滤器过滤。
试剂制备:从Fujirebio购得ACE彩色套件,根据生产者的说明进行试验:用5.6ml的缓冲液重建基质,用5.6ml的缓冲液重建对照,用15.5ml的滴液(stopper solution)重建显色剂。鼠肺ACE(Sigma A6778)重构成1单位/3ml水的浓度。
试验方法:根据下表,将它们分别不同的量加入到样品或对照试管中,以测定血清和组织ACE的最佳浓度。
0 2.5 5 10 15 20 μL血清
5 10 25 50 μL组织ACE
然后加入基质或对照溶液(125μL),在37℃培养20分钟。加入显色剂溶液,在37℃培养3分钟。通过在分光光度计上测定505nM吸光度来测定测试化合物的活性。血清ACE(25μL)和组织ACE(3.3m单位)的最佳量用于测定铼标记的ACE抑制剂的特异性。制备测试化合物,包括赖诺普利和卡托普利(50μM备料),并逐次稀释10倍,最终的浓度范围为1μM-0.1nM(10μL/试管)。如上所述进行试验。
表1:选择的肽酶和肽酶的基质
羧肽酶A1
基质:
Bz-Gly-Phe
Dns-Gly-Gly-Phe
Dns-Gly-Gly-Trp
Dns-Gly-Phe
Dns-Gly-Trp
Z-Gly-Gly-Leu
Z-Gly-Gly-Phe
Z-Gly-Gly-Val
羧肽酶A2
基质:
Z-Gly-Gly-Leu
Z-Gly-Gly-Phe
Z-Gly-Gly-Trp
Z-Gly-Trp
羧肽酶B
基质:
Bz-Gly-Arg Bz-Gly-基s
呋喃丙烯酰基-Ala-Arg
肥大细胞羧肽酶A
羧肽酶D
基质:
丹酰-Phe-Ala-Arg
羧肽酶E
羧肽酶G,羧肽酶G1,羧肽酶G2
基质:
叶酸
羧肽酶M
羧肽酶N
羧肽酶Y
基质:
Z-Gly-Leu
羧肽酶Z
羧肽酶T
Serine羧肽酶A
基质:
Bz-Tyr-OEt
丹酰-D-Tyr-Val-NH2
呋喃丙烯酰基-Phe-Phe
Z-Glu-Tyr
Z-Phe-Ala
Z-Phe-Leu
Z-Phe-Phe
表2:所选择肽酶的小分子抑制剂
141W94
4-羟基-5,6-二氢-2-吡喃酮衍生物
ABT-378
ABT-538
Ac-Asp-Glu-Val-Asp-H
Ac-DEVD-CHO
Ac-Ile-Glu-Thr-Asp-H
Ac-Leu-Leu-Arg-H
Ac-Leu-Leu-Met-H
Ac-Leu-Leu-Nle-H
Ac-PRLNvs
Ac-Pro-Arg-Leu-AsnVS
Ac-Trp-Glu-His-Asp-H
Ac-Tyr-Val-Ala-Asp-H
Ac-WEHD-CHO
Ac-YVAD-CHO
脑啡肽酶抑制剂(前体)
N-乙酰基-天冬氨酰基-谷氨酰基-异戊氨酰-天冬氨酸甲醛
N-乙酰基-L-亮氨酸-L-亮氨酸-D,L-a精氨酸甲醛
N-乙酰基-色氨酰基-谷氨酰基-组氨酸基-天冬氨酸甲醛
放线酰胺素
活性代谢物M8
Ada-Ahx3-L3VS
AdaAhx(3)L(3)VS
AEBSF
AG-1343
AG7088
安瑞那韦
AGM-1470
阿利克仑
ALLM
ALLN
allophenylnorstatine-包含抑制剂
抑氨肽酶肽
[(2S,3R)]-3-氨基-2-羟基-5-甲基己酰基]-Val-Val-Asp
2-(5-氨基-6-氧-2-苯基-嘧啶-1-基)-N-[1-羟基-3-甲基-1-(5-叔丁基-1,3,4-噁二唑-2-基)丁烷-2-基]乙酰胺
2-氨基-N-[5-(6-二甲基氨基嘌呤-9-基)-4-羟基-2-(羟甲基)草脲胺-3-基]-3-(4-甲氧苯基)丙酰胺
安普那韦
抗蛋白酶
apstatin
替拉那韦
阿加曲班
奥代美宁A
奥代美宁B
阿扎那韦
azido苯丁抑制素
杆菌肽A
巴马司他
BB-2516
BB-94
苯甲脒
{1S-苯甲基-4R-[1-(1S-氨基甲酰-2-苯乙基氨基甲酰)-1S-3-甲基丁基氨基甲酰]-2R-羟基-5-苯戊基}氨基甲酸叔丁基酯
苯甲氧羰基羰苯基丙氨酰精氨酰重氮甲烷
苯甲磺酰氟
苯丁抑制素
苯丁抑制素类似物SL-387
苯丁抑制素,含硫类似物
BILN2061
BMS-232632
BMS186716
Boc-Ile-Glu-Thr-Asp-H
硼替佐米
贝卡那韦
butabindide
N-[2-[5-(叔丁基)-1,3,4-噁二唑-2-基]-(IRS)-1-(甲乙基)-2-氧乙基]-2-(5-氨基-6-氧-2-苯基-6H-嘧啶-1-基)乙酰胺
(2S)-N-[(2S,3R)-4-[(3S,4aS,8aS)-3-(叔丁基氨基甲酰)-3,4,4a,5,6,7,8,8a-八氢-1H-异喹啉基-2-基]-3-羟基-1-苯基-丁烷-2-基]-2-(喹啉基-2-羰氨基)丁二酰氨
Bz-Leu-Leu-Leu-COCHO
BzLLLCOCHO
CA074
钙蛋白酶抑制剂I
钙蛋白酶抑制剂II
钙蛋白酶抑制剂III
坎沙曲
坎沙曲拉
卡托普利
N-[(S)-1-羧基-3-苯丙基]-L-Ala-L-Pro
组织蛋白酶L抑制剂
CGP-60536
对-氯汞基苯甲酸盐
糜蛋白酶抑制剂
西司他汀
CKD-731
clasto-乳胞素beta-lactone
CLIK148
CRA-013783
Crixivan
(1S,4R,6S,7Z,14S,18R)-14-环苯氧羰氨基-18-[2-(2-异丙氨基-噻唑-4-基)-7-甲氧喹啉基-4-氧基]-2,15-二氧-3,16-二氮杂三环[14.3.0.04.6]十九烷-7-烯-4-羧酸
D-2-甲基-3-巯基丙酸基-L-Pro
D-Phe-Pro-Arg-CH(2)Cl
DANLME
DAPT
地瑞拉韦
DCI
DFP
1,3-二-(N-苄氧羰基-L-亮氨酸-L-亮氨酸)氨基丙酮
重氮乙酰基-D,L-己氨酸甲酯
3,4-二氯异香豆素(DCI)
N-[N-(3,5-二氟苯乙酰基)-1-丙氨酰]-S-苯甘氨酸叔丁酯
二异丙基氟磷酸酯(DFP)
二异丙基氟膦酸
(2S)-N-[(2S,4S,5S)-5-[[2-(2,6-二甲基苯氧基)乙酰基]氨基]-4-羟基-1,6-di苯基-己烷-2-基]-3-甲基-2-(2-氧-1,3-二嗪磷-1-基)丁酰胺
N-[2-[4-(2,2-二甲基丙酸基)苯磺醯胺基]甘氨酸
4,6-二氧二环[3.3.0]八-8-基[4-[(4-氨苯基)磺酰基-(2-甲丙基)氨基]-3-羟基-1-苯基-丁烷-2-基]氨基甲酸
DPC423
DX-9065a
E-64
E64
E64c
E64d
EDTA
Elaspol
弹性(蛋白)酶抑制剂
依那普利
依那普利拉
Ep475
EPNP
1,2-环氧基-3(p-硝苯氧基)丙烷
EST
N-(2-乙氧基-5-氧-草脲胺-3-基)-5-异喹啉基-1-基羰氨基-2,6-二氧-1,7-二氮杂二环[5.4.0]十一烷-8-羰酰胺
1-[2-(1-乙氧羰基-3-苯基-丙基)氨基丙酰基]吡咯烷-2-羧酸
乙基(+)-(2S,3S)-3-[(S)-3-甲基-1-(3-甲基丁基氨基甲酰)丁氨基甲酰]-2-环氧乙烷羧酸酯
N-顺丁烯二酰亚胺
1-乙基吡咯-2,5-二酮
3-(5-氟-3-吲哚)-2-巯基-(Z)-2-丙烯酸
4-[2-[(4-氟苯基)甲基]-6-甲基-5-(5-甲基噁唑-3-基)羰氨基-4-氧-庚酰]氨基-5-(2-氧吡咯烷-3-基)-五-2-enoate
N-甲酰-allo-Ile-Thr-Leu-Val-Pip-Leu-Pip
N-甲酰-Val-Thr-Leu-Val-Pip-Leu-Pip
2-[2-(甲酰-{同分异构}-异亮氨酸-苏氨酰-亮氨酸-异戊氨酰)-(六氢哒嗪-3-羰基)-亮氨酸]-六氢哒嗪-3-羧酸
沙奎那韦
福斯安普那韦(前体)
FPRCH2Cl
fumagalone
烟曲霉素
γ-分泌酶抑制剂II
球霉素
GW0385
GW433908
GW433908(前体)
HMBA
HMBSA
1R-[1S,4R,5S]-1-(1-羟基-2-甲内基)-4-丙基-6-噁-2-氮杂二环[3.2.1.]正庚烷-3,7-二酮
(3S,4aS,8aS)-2-[(2R,3R)-2-羟基-3-[(3-羟基-2-甲基-苯甲酰)氨基]-4-苯磺酰-丁基]-N-叔丁基-3,4,4a,5,6,7,8,8a-八氢-1H-异喹啉基-3-羰酰胺
(4R)-3-[(2S,3S)-2-羟基-3-[[(2R)-2-[(2-异喹啉基-5-基氧乙酰基)氨基]-3-甲磺酰-丙酰基]氨基]-4-苯基-丁酰基]-N-叔丁基-噻唑烷-4-羰酰胺
[1-[[3-羟基-4-[(2-甲氧基羰氨基-3,3-二甲基-丁酰基)氨基-[(4-吡啶-2-基苯基)甲基]氨基]-1-苯基-丁烷-2-基]氨基甲酰]-2,2-二甲基-丙基]氨基甲酸
3-羟基-4-[2-[3-羟基-6-甲基-4-[3-甲基-2-[3-甲基-2-(3-甲基丁酰基氨基)丁酰基]氨基-丁酰基]氨基-庚酰]氨基丙酰基氨基]-6-甲基-庚酸
(2S)-1-[(2S,4R)-2-羟基-4-[[(1S,2R)-2-羟基-2,3-二氢-1H-茚-1-基]氨基甲酰]-5-苯基-pentyl]-4-(吡啶-3-基甲基)-N-叔丁基-哌嗪-2-羰酰胺
N-[3-[(1R)-1-[(6R)-2-羟基-4-氧-6-苯乙基-6-丙基-5H-吡喃-3-基]丙基]苯基]-5-(三氟甲基)吡啶-2-磺酰胺
p-羟基汞苯磺酸酯
p-羟基汞安息香酸酯
IDN-6556
茚地那韦
invirase
碘代乙酰胺
碘代醋酸酯
2-碘代醋酸酯
碘代泰诺司他汀
异戊酰-L-酪氨酰-L-异戊氨酰-DL-酪氨酸
N-异戊酰-酪氨酰-亮氨酸-酪氨酸
KNI-272
凯诺司他汀-272
L-006235
L-709049
L-735,524
L685458
乳胞素
LAF237
亮抑酶肽
洛匹那韦
洛伐他汀
LY-570310
马立马司他
MD805
MDL28170
[3-甲基-1-(3-苯基-2-吡嗪-2-基羰氨基-丙酰基)氨基-丁基]硼酸
4-甲基伞型酮p-(NNN-三甲基铵)肉桂酸
4-甲基伞型酮p-胍基苯甲酸酯
MG-101
MG-262
MG132
MK-421
MK-422
MK-639
MK0791
MLN-341
MLN519
MQPA
MUGB
MUTMAC
MW167
N-[(S)-2-苯甲基-3[(S)(2-氨基-4-甲基硫)丁基二硫]-1-氧丁基]-L-苯丙氨酸苯甲酯
奈非那韦
NEM
Nip-Leu-Leu-LeuVS-Me
硝苯丁抑制素
NLVS
Norvir
NPGB
NPI-0052
NVP-LAF237
奥马屈拉
omuralide
ONO-5046
ONO-6818
OP
卵假散囊素
6-氧-5-(3-苯基-2-硫烷基-丙酰基)氨基-2-硫-7-氮杂二环[5.4.0]十一烷-8-羧酸
6-氧-6-去氧烟霉醇
草脲胺-3-基[4-[(4-氨苯基)磺酰基-(2-甲丙基)氨基]-3-羟基-1-苯基-丁烷-2-基]氨基甲酸
p-硝苯基-p’-胍基安息香酸酯
PCMB
PD150606
PD151746
Pefabloc
抑肽素
抑肽素A
1,10-邻二氮杂菲
o-邻二氮杂菲
苯甲磺酰基氯化物
2-(磷酰甲基)戊二酸
磷酰二肽
派普拉司他汀
派普拉司他汀A
PMPA
PMSF
PNU-140690
普思特司他汀
PPACK
pralnacasan
N-(L-3-顺-丙基氨基甲酰环氧乙烷-2-羰基)-L-异亮氨酸-L-脯氨酸
蛋白酶体抑制剂3
蛋白酶体抑制剂III
PS-519
PS341
假-碘代泰诺司他汀
假-泰诺司他汀
PSI-3
PSI-III
嘌呤霉素
RB 101(S)
后-塞奥芬[[[(R)-1-(巯甲基)-2-苯乙基]氨基]-3-氧丙酸]
[HSCH2CH(CH2C6H5)NHCOCH2COOH]
利托那韦
RK-805
Ro 31-8959
芦平曲韦
ruprinttivir
S-PI
S17092
salinosporamide A
沙奎那韦
SCH 503034
SCH446211
SCH6
sivelestat
SPP100
SQ14225
SSR69071
他汀类药物
TBL(4)K
1,3-噻唑-5-基甲基[[3-羟基-5-[[3-甲基-2-[[甲基[(2-丙烷-2-基-1,3-噻唑-4-基)甲基]氨基甲酰]氨基]-丁酰基]氨基]-1,6-二苯基-己烷-2-基]氨基]甲酸酯
塞奥芬
塞奥芬[N-[(S)-2-(巯甲基)-1-氧-3-苯丙基]甘氨酸]
[HSCH2CH(CH2C6H5)CONHC-H2COOH]
tipranavir
TLCK
TMC-95
TMC-95A
TMC-95B
TMC-95C
TMC-95D
TMC114
TNP-470
Tos-基CH(2)Cl(TLCK)
Tos-PheCH(2)Cl(TPCK)
TPCK
L-顺-乙氧基琥珀酰-亮氨酸酰氨基(3甲基)丁烷
L-顺-乙氧基琥珀酰-亮氨酸酰氨基(4-胍基)丁烷
硫肽酶素A
硫肽酶素B
泰诺司他汀
泰诺司他汀
Ubenimex
UIC-94017
UK-69,578
UK-73,967
UK-79,300
Velcade
维格列汀
Viracept(奈非那韦甲磺酸酯)
VX-740
VX478
VX950
Z-Leu-Leu-leucinal
Z-Leu-Leu-LeuVS
(Z-LL)(2)酮
Z-Phe-Arg-重氮甲烷
Z-Val-Phe-H
ZD-8321(中性粒细胞弹性蛋白酶)
ZL(3)VS
ZL3VS
通过多种方法可以评价其它有意义肽酶潜在的抑制剂。下面提供了一些示例性的科学试验计划。
羧肽酶A1和A2
羧肽酶A(CPA)是一种水解和多肽链C-末端相连的肽键的胰脏金属肽酶。羧肽酶A1(CPA1)和羧肽酶A2(CPA2)的区别在于针对具体的肽基质:前者(可认定为传统的A型)对脂肪族和芳香族残基有更好的优势,而后者对芳香族残基更苛刻。具有芳香族或支侧链的C-末端L-氨基酸优选从肽链上分裂。
反应速度取决于Folk和Schirmer(1963)方法。参考Folk,J.和Schirmer,E.J.Biol.Chem.(1963)238:3884-94。通过测定在254nm处吸收的增加来确定马尿酰-L-苯丙氨酸(Sigma H6875)的水解率。在具体的条件、25℃和pH 7.5下,1单元每分钟水解1微摩尔的马尿酰-L-苯丙氨酸。
基质
1mM的马尿酰-L-苯丙氨酸和0.5M氯化钠一起溶于pH为7.5、25mM的甲烷盐酸盐中。
酶
可以从Sigma(C5358)购买CPA1。相应的,根据Laethem等人的ArchBiochem Biophys(1996)332(1):8-18公开的步骤提纯hCPA1。根据Reverter等人的J.Biol.Chem.(1998)273(6):3535-41公开的步骤提纯hCPA2。
步骤
将原料CPA溶液溶于10%的氯化锂中,得到的最终浓度为1-3单位/mL。CPA的浓度可以通过测定278nm(mg/mL=A278x0.515)处的吸收率来计算。基质为试验缓冲液(25mM甲烷盐酸盐,0.5M氯化钠,pH 7.5)中的马尿酰-L-苯丙氨酸(1mM)。用移液器吸取2.0mL的基质移送到小玻璃管中,于25℃在分光光度计中培育3-4分钟,达到温度平衡,并建立空白速率(如有)。加入0.1mL稀释的酶,在3-5分钟内记录A254中的增加。从曲线起始的直线部分测定Δ254/分钟。测试化合物的抑制活性通过测试浓度范围为1μM-0.1nM的反应速率来分析。
计算
*0.36=反应期间形成的马尿酸的消光系数
采用Worthington Biochem中的试验。更多参考请参照:
羧肽酶B
羧肽酶B(CPB)催化碱性氨基酸赖氨酸、精氨酸和鸟氨酸从多肽的C-端水解。用Folk和Schirmer(1963)的分光光度方法测定活性,其中的反应速率通过由马尿酰-L-精氨酸水解导致在254nm出吸收率的增加来测定。在具体的条件、25℃和pH 7.65的情况下,一单位导致每分钟1微摩尔的马尿酰-L-精氨酸水解。
基质
1mM的马尿酰-L-精氨酸在含有0.1M氯化钠的25mM甲烷盐酸盐、pH 7.65中。
酶
可以通过Sigma(C9584)购买CPB。将原料溶液用反应级的水系数,浓度达到1-5单位/mL。
步骤
用移液器吸取2.9mL的基质移送到小玻璃管中,于25℃在分光光度计中培育3-4分钟,达到温度平衡,并建立空白速率(如有)。加入0.1mL稀释的酶,在3-4分钟内记录A254中的增加。从曲线起始的直线部分测定ΔA254/分钟。测试化合物的抑制活性通过测试浓度范围为1μM-0.1nM的反应速率来分析。
计算
*反应期间形成的马尿酸的消光系数
采用Worthington Biochem中的试验。更多参考请参照:
Sigma-Aldrich中的另一替代机理如下:
http://www.sigmaaldrich.com/img/assets/18160/carboxypcptid
ase B.pdf#search=%22 carboxypeptidase%20b%20assay%22
羧肽酶D
羧肽酶D(CPD)是180-kDa的单链醣蛋白,其具有三个一样的羧肽酶活性位域和羧基端疏水穿膜标记。其从蛋白质和肽的羧基端分裂单氨基酸,该蛋白质和肽显示了对羧基端精氨酸或赖氨酸严格特异性。
基质
CPD基质丹酰-L-丙氨酰-L-精氨酸通过丹酰氯和前述的二肽、丙氨酸-精氨酸反应进行合成。参考:Proc.Natl.Acad.Sci.U.S.A.(1982)79:3886-3890;Life Sci.(1982)31:1841-1844;MethodsEnzymol.(1995)248:663-675。
酶
在MCF-7细胞溶菌液中测定CPD活性。MCF-7细胞[(10-20)×106]在0.1M的乙酸钠缓冲液(pH 5.6)中用21-规的针均质化。制备总的细胞溶菌液或亚细胞组分,每个组分中加入Triton X-100,得到最终的浓度0.1%(v/v)。直至进一步的分析,样品在-20℃保存。
步骤
冰冷的酶样品(在总体积50μL中的60-80ng蛋白质/μL)在37℃、150μL的0.1M的乙酸钠缓冲液(pH 5.6)预培养5分钟。通过加入预平衡的(37℃)丹酰-L-丙氨酰-L-精氨酸基质(在50μL的0.1M乙酸钠缓冲液中,pH 5.6)启动试验。37℃培育(CPD-N经过6分钟,CPD经过10分钟)后,加入150uL的1M柠檬酸终止反应,样品放在冰中。用氯仿萃取,从亲水性基质丹酰-L-丙氨酰-L-精氨酸中分离出丹酰-L-丙氨酸产品。在340nm的激发波长和495nm放射处,相对于氯仿空白测试了氯仿层中的荧光。使用不同浓度的丹酰-L-丙氨酸(Tokyo Chemical Industry America,Portland,OR,U.S.A.),构建每个试验的标准曲线,以校对萃取效率中的波动。使用的抑制剂为MGTA(DL-2-巯甲基-3-胍乙基硫代丙酸(Calbiochem,La Jolla,CA,U.S.A.)和OP(1,10-邻二氮杂菲;Sigma)。CP的活性通过存在或不存在10μM MGTA的活性差异进行测定。SA的具体活性计算为Vmax(μmol/分钟=单位)每mg蛋白质(即SA=单位/mg蛋白质)。Km为63uM,Vmax=27umol/分钟。所测试化合物的抑制活性在浓度范围0.1uM-0.1nM内分析。
参照:Biochem J.(2005)390(Pt 3):665-73
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=p
ubmed&pubmedid=15918796
羧肽酶E
羧肽酶E(CPE)是一种处理酶,该酶从内蛋白水解分裂的肽荷尔蒙的C-端分裂碱性残基。该酶不在神经细胞和内分泌细胞中的高尔基体和分泌颗粒中出现。
基质
Dns-Phe-Ala-Arg可以通过Fricker的Methods Neurosci.(1995)23:237-250中的方法制备。
酶
羧肽酶E可以用上述建立的步骤进行提纯和分离。参考:J.Biol.Chem.(1996)271(8):30619-30624.
步骤
对于羧肽酶测定,25μL的酶和50mM NaAc、pH 5.5和200μM丹酰-Phe-Ala-Arg基质合并,最终体积为250μL。此外,试管中含有1mMCoCl2或1μM胍乙基巯基琥珀酸(GEMSA)。样品和抑制剂在4℃下预培养15分钟,然后加入基质,试管在37℃下预培养1小时。接着培养60分钟,加入100μL的0.5M HCl和2mL的氯仿,在试管中混合,然后在500×g离心2分钟。通过氯仿层中测试的荧光(激发350nm,发射500nm)测定产品的量。金属羧肽酶活性定义为Co2+(CPE的活化剂)存在时的活性和GEMSA(CPE的抑制剂)存在时的活性之间的差值。对于这些试验,羧肽酶的活性定义为含有酶的试管和仅有缓冲液和基质的试管之间的荧光的差值,表示为含有酶、缓冲液和基质的对照试管的%,但是不含有二价离子或抑制剂。测试化合物的抑制活性在浓度范围为1μM-0.1nM.之间分析。
参考:J.Biol.Chem.(1996)271(8):30619-24
http://www.jbc.org/cgi/content/full/271/48/30619?ijkey-911
4ecbb2b0629a51b4b2c5782deeec9ed63a931
羧肽酶G
羧肽酶G为溶酶体、硫醇依赖性蛋白质酶,其逐渐分裂g-谷氨酰基蝶酰基聚-g-谷氨酸酯,得到蝶酰基-a-谷氨酸酯(叶酸)和游离的谷氨酸。羧肽酶G被认为对g-谷氨酰基键高度特异性,但是对分离基团的C-端氨基酸不是(参考:J.Biol.Chem.(1967)242:2933)。
基质
可以从Sigma-Aldrich(A7019)购买(+)氨甲喋呤。
酶
羧肽酶G可以从Sigma-Aldrich(C9658)购买。在pH 7.3、30℃的条件下,一个单位每分钟从(+)氨甲喋呤水解1.0微摩尔的谷氨酸。
步骤
在pH7.3、30℃的条件下,将2.8mL、50mM的Tris HCl缓冲液和0.1mM的氯化锌加入到0.1mL 1.8mM的(+)氨甲喋呤中。倒转混合,平衡到30℃。检测A320nm,直至稳定,用合适的恒温器分光光度计。然后加入含有0.3-0.6单位/mL水的0.1mL酶。立即倒转混合,用测试和空白的最大线速度记录Δ320nm/分钟的减少。测试化合物的抑制活性在浓度范围为1μM-0.1nM.之间分析。
计算
3=测试体积(毫升)
df=稀释因子
8.3=320nm处基质和产品之间在毫摩尔消光系数中的差值
10.1=使用的酶体积(毫升)
参考Sigma-Aldrich酶测定:
http://www.sigmaaldrich.com/sigma/enzyme%20assay/c9658enz.
pdf
羧肽酶M
羧肽酶M(CPM)是一种细胞外糖基磷脂酰肌醇标记的膜糖蛋白。该蛋白质属于锌金属羧肽酶的CPN/E子类。它具体从含有次末端丙氨酸的肽上除去C-端碱性残基,如赖氨酸和精氨酸。确信的是,该羧肽酶对控制细胞表面上的肽荷尔蒙和生长因子活性起着重要作用,以及在细胞外蛋白质(Braz J Med Biol Res 200639:211-217)的膜定位降解中起着重要作用。
基质
通过丹酰化二肽Ala-Arg合成丹酰-Ala-Arg(Methods inNeurosciences:Peptide Technology″(P.M.Conn,ed.),Vol.6,p.373.Academic Press,Orlando,Florida,1991)。
酶
羧肽酶M根据Tan等人说明的发进行分离、提纯(Methods Enzymol1995 248:663-675)。
步骤
加入125uL的缓冲液(0.2M HEPES[4-(2-羟乙基)-1-哌嗪乙二酸],pH 7.0,含有0.2%(v/v)Triton X-100)、5-50/uL的酶样品、0或25μL的100uM的MGTA和0-70μL的水,最终的体积为200μL。对于每套反应,准备一个酶空白(没有基质)和一个基质空白(没有酶)。为了确保反应的特异性,样品可以用与不用2-巯甲基-3-胍乙基硫代丙酸(MGTA)抑制剂进行预培养。样品在冰上预培养5-10分钟,然后加入50uL的1.0mM丹酰-Ala-Arg(4.64mg/10mL水或稀释10mM原料溶液1∶10)开始反应。根据活性,在37℃培养样品15分钟到3个小时,燃用加入150uL的停止溶液(用氢氧化钠调整为pH为3.1的1.0M柠檬酸)终止反应。每个试管中加入氯仿(1.0mL),激烈混合15秒,萃取丹酰-Ala产品,然后在约800g时离心10分钟,分离相。氯仿层的荧光(底层)相对于氯仿空白在340nm的激发波长和495nm的发射波长进行测试。测试化合物的抑制活性在浓度范围为1μM-0.1nM.之间分析。
计算
羧肽酶活性定义为未抑制样品和用10mM MGTA抑制的样品之间在荧光中的差值。荧光单位(FU)通过构建FU对丹酰-Ala(Sigma D0125)浓度的标准曲线转换为毫微摩尔基质。
参考:Methods Enzymol(1995)248:663-675。
羧肽酶N
羧肽酶N(CPN)为血浆锌金属蛋白酶,其由两个酶活性的小亚组(CPN1)和防止蛋白质分解的两个大亚组(CPN2)组成。CPN从血液中发现的含有次末端丙氨酸的肽上分裂羧基端的精氨酸和赖氨酸,如补充的过敏毒素、激肽和肌酸激酶MM(CK-MM)。通过除去仅有的一个氨基酸,CPN有能力改变肽活性和受体结合(Mol Immunol(2004)40:785-93)。
基质
呋喃丙烯酰基(FA)-Ala-yls从Sigma(F5882)商业购得。
酶
根据Skidgel的Methods Enzymol(1995)248:653-63中的方法提纯羧肽酶N。
步骤
加入0.5mL含有0.5M的NaCl缓冲液的0.1M HEPES(pH 7.75)、0.1mL的5mM FA-Ala-yls(18.23mg/10mL水)和足够的水,最终得到的体积为1.0mL(包括样品)。在水浴中将混合物温热到37℃,简单混合时加入酶样品,然后将溶液快速输送到记录分光光度计的恒温器(37℃)中的预热小槽中。336nm处的吸收变化连续记录约2-3分钟。测试化合物的抑制活性在浓度范围为1μM-0.1nM.之间分析。
参考:Methods Enzymol(1995)248:653-63。
羧肽酶T
发现羧肽酶T(CPT)由普通高温放线菌分泌。CPT对肽基质的特异性合并了羧肽酶A和B的特点,即,该酶分裂C-端中性基团,优选为疏水的氨基酸,如羧肽酶A,以及分裂它们侧链中产生正离子基团的精氨酸和赖氨酸残基。
酶
根据Stepanov的Methods Enzymol(1995)248:675-83中的方法提纯羧肽酶T。
基质
通过前述的步骤完成Dnp-Ala-Ala-Arg-OH的合成。参考Biokhimiya(1973)38:790。
步骤
在0.1M Tris-HCl缓冲液、pH 7.5、10-100μL的酶溶液中加入1mL的0.5mM基质溶液。混合物在37℃培养10-60分钟,然后加入0.2mL的50%CH3COOH中止反应。混合物定量的转移到含有2mL的SPSephadex C-25的微型柱(塞有棉花的Eppendoff自动移液器的塑料圆锥)中,用1M的CH3COOH预平衡。柱子用1M的CH3COOH清洗(两次,1mL)。合并洗液,测定溶液的A360。为了计算Dnp-Ala-Ala-OH浓度,使用的摩尔消光值(e360)为15,000。一个活性单位等于在具体的条件下于1分钟内水解1~mol基质的酶的量。测试化合物的抑制活性在浓度范围为1μM-0.1nM.之间分析。
参考:Methods Enzymol(1995)248:675-683。
羧肽酶Y
羧肽酶Y(CPDY)酿酒酵母中分离的64kDa丝氨酸羧肽酶,已经发现该酶能催化多种离去基团的水解反应,如氨基酸、对硝基苯胺和多种醇。试验测定了在酶水解苄氧羰基-L-苯基丙氨酰-L-亮氨酸过程中亮氨酸的离去速度。
基质
苄氧羰基-L-苯基丙氨酰-L-亮氨酸可以从Sigma(C1141)处购买。注:和缓冲液混合前,0.5mL的DMSO(二甲亚砜)可以用于溶解苄氧羰基-L-苯基丙氨酰-L-亮氨酸。
酶
羧肽酶Y从Sigma(C3888)购买。用反应级的水制备1mg/mL的酶溶液。
步骤
在50mM的磷酸钠、0.15M氯化钠和pH为6.5的基质溶液中加入1.0mL的1mM苄氧羰基-L-苯基丙氨酰-L-亮氨酸。在25℃中预培养10分钟。加入50uL的酶开始酶反应。反应在25℃中反应10分钟。加入1.0mL的茚三酮试剂(通过混合50mL在甲基纤维素中的4%的茚三酮和0.2M的柠檬酸钠(pH 5.0)-7.1mM的氯化亚锡)。将10个测试试管中的每一个搅拌15分钟。将所有的试管放在开水中水浴15分钟。从水浴中移走试管,冷却到低于30℃。在每个测试试管中加入5.0mL、50%的丙醇溶液,并充分混合。在570nm处读取所有试管的光密度。使用不同浓度的亮氨酸,构建每个试验的标准曲线。测试化合物的抑制活性在浓度范围为1μM-0.1nM.之间分析。
计算:
参考Worthington Biochem。请参考:
http://www.worthington-biochem.com/COY/default.htmL
羧肽酶Z
羧肽酶Z(CPZ)属于金属羧肽酶的羧肽酶E子类。尽管这些Zn依赖酶通常不是公知的CPZ具体的基质、包含在蛋白质的细胞内处理和细胞外外处理中,但是其已显示出分裂C-端精氨酸,以及包含在Wnt信号通道中。参考Development(2003)130(21):5103-11。
基质
丹酰-Phe-Ala-Arg可以通过Fricker的方法进行制备:MethodsNeurosci.(1995)23:237-250。
酶
如同以前报道的一样,通过亲合色谱法提纯,羧肽酶Z cDNA能够转染成AT-20细胞和蛋白质。参考:Biochem Biophys Res Comm.(1999)256:256-8。
步骤
CPZ活性在最终体积为250uL、100mM、pH 7.4、Tris-HCl缓冲液中用0.2mM丹酰-Phe-Ala-Arg测定。在37℃中3小时后,反应用100μL、0.5M的HCl终止,然后加入2mL的氯仿。混合后,以300xg离心2分钟,通过测定氯仿相中的荧光测定产品的量。为了检测抑制剂的效果,在缓冲液、基质和抑制剂的混合物中加入提纯的CPZ,得到最终浓度为50mM Tris-Cl,pH 7.4,100uM丹酰-Phe-Ala-Arg和所示浓度的抑制剂。反应在37℃中培养1小时。培养后,加入100μL的0.5M HCl和2mL的氯仿,试管混合,然后以500×g离心2分钟。通过测定氯仿层中的荧光(激发350nm、发射500nm)测定产品的量。进行没有酶的对照反应。进行大量CPE的反应,以测定对应于基质完全转化为产品的荧光。Km值用丹酰-Phe-Ala-Arg和丹酰-Pro-Ala-Arg测定,使用的浓度范围为0.025-1.6mM。参考:Biochemical and Biophysical Research Communications(1999)256:564-568。
丝氨酸羧肽酶A
丝氨酸羧肽酶A也称之为哺乳动物组织蛋白酶A,溶酶体羧肽酶A和溶酶体保护性蛋白定义为能在酸性pH中水解Z-Glu-Tyr的酶。该酶也显示了在中性pH中的酯酶和脱酰胺酶的活性。由于组织蛋白酶A能在体外水解大量合成的生物活性的肽激素,如Z-Phe-Leu、血管紧缩素II、物质P和内皮素,已经建议组织蛋白酶A可以包含在太激素的体内代谢中,尽管对组织蛋白酶A的胜利基质还不清楚。HPLC分离后,组织蛋白酶A的活性的测定机理基于从基质中酶脱离的N-DNS-Phe的荧光测定、N-DNS-Phe-Leu。
酶
以100,000xg离心80分钟的蔗糖中0.25M的鼠肾匀浆用于酶源。
基质
根据Wiedmeier的J.Chromatogr.(1982)231:410公开的方法合成N-DNS-Phe-Leu。
步骤
反应混合物包括50mM的乙酸钠缓冲液(pH 4.6)、40μM的N-DNS-Phe-Leu和酶、水,总的反应体积为250uL。培养在37℃中进行,通过在95℃的开水中加热5分钟终止反应。离心后,在清澈的上清液中加入N-DNS-NLeu作为内部标准,得到的等份混合物根据Chikuma等人的J Chrom B:Biomed Sci and Apps(1999)728(1):59-65进行HPLC分析。测定N-DNS-Phe的峰高,并从N-DNS-NLeu内部标准的峰高转化为微微摩尔。一单位的酶活性定义为在37℃、1分钟内将1pmol的基质转化为相应产品所需的酶的量。测试化合物的抑制活性在浓度范围为1μM-0.1nM.之间分析。.参考:J.Chrom.B:Biomed.Sci.andApps.(1999)728(1):59-65。在含有溶入甲醇(xx mL)的D(Cx)L(1eq)的圆底烧瓶中加入[Re(CO)3(H2O)3]Br(1eq)。反应加热到80℃,并搅拌4小时。除去冷却的容积后,样品用HPLC提纯。样品用1H NMR和质谱分析。
Re(CO)3D(C4)L(5):产量=23%(0.4g)。1H NMR(CDCl3,ppm):8.77(m,2H),7.91(m 2H),7.61(m,2H),7.35(m,2H),7.13(m,5H),5.00(m,4H),4.12-2.60(mm,11H),2.26-1.41(mm,16H)。MS(ESI):m/z 944(M+H)+,m/z 942(M-H)+。
Re(CO)3D(C5)L(6):产量=34%(0.61g)。1H NMR(CDCl3,ppm):8.77(m,2H),7.91(m 2H),7.61(m,2H),7.35(m,2H),7.13(m,5H),3.92(d,4H),3.69-2.65(mm,11H),2.27-1.46(mm,18H)。MS(ESI):m/z 688(M+H)+,m/z 686(M-H)+。
Re(CO)3D(C8)L(7):产量=55%(0.40g)。1H NMR(CDCl3,ppm):8.50(d,2H),7.63(m 2H),7.50(m,2H),7.13(m,8H),3.85(d,4H),3.69-2.53(mm,11H),2.23-1.22(mm,24H)。MS(ESI):m/z730(M++H)+.m/z728(M-H)+。
99mTc(CO)3D(Cx)L的一般步骤
用公开的文献[6]通过Isolink试剂盒制备[99mTc(CO)3(H2O)3]+。为了测试金属络合物的鼠血浆稳定性,分离的99mTc(CO)3D(Cx)L在37℃、1mL的鼠血浆中培养5分钟、60分钟和24小时。在所需的时间点,除去等份的培养混合物(400μL)。乙腈(800L)的加入产生了沉淀,该沉淀在15,000rpm离心5分钟。除去上清液,在氮气流中浓缩。剩下的残基溶于10%乙醇/盐水,并用HPLC分析,以测定化合物的稳定性(图4)。
体外ACE活性试验。根据生产者的说明,测试化合物抑制ACE活性的能力用Fujirebio,Inc.的ACEeolor试剂盒测定。提纯的鼠肺ACE()在37℃和测试化合物一起培养20分钟,测试化合物在基质溶液中的浓度为1 M-0.1nM。加入显影剂溶液,在分光光度计、505nm读数前,样品在37℃再培养5分钟。
鼠组织分布。99mTc(CO)3D(C8)L(MIP-1037)的组织分布研究在单独的雄性大白鼠(n=5/时间点)组中进行。MIP-1037以50μCi/kg从尾部静脉团注(约10μCi/rat),体积恒定为0.1ml。在注射10分钟、30分钟、1小时和2小时后,用二氧化碳对这些动物进行安乐死。将组织(血液、心肺、肝脏、脾、肾、大肠和小肠(含有内容物)、睾丸、骨骼肌和脂肪)分离、切割、称湿重,转移到塑料试管中,用自动的γ-计数器(LKB Model 1282,Wallac Oy,Finland)计数。表达为%ID/g、99mTc(CO)3D(C8)L(MIP-1037)的组织时间-放射性水平通过每分钟校正计数的衰减转化为百分比剂量和除以组织或器官样品的重量来测定。也测定等份的注射剂量,将每个组织样品中的每分钟计数转化为每个器官中注射剂量的百分比。
成像。用戊巴比妥钠(50mg/kg,i.p)对6个大白鼠进行麻醉,随意分配到99mTc(CO)3D(C8)L(MIP-1037)或赖诺普利/99mTc(CO)3D(C8)L(MIP-1037)治疗组(n=3/组)。所有的6个动物放在γ-照相机上,基线平面腹部成像由5个组成,对于单个动物,一分钟连续成像用低能量DSX-LI双头γ-照相机、通用瞄准器(SMV America)和迷你γ-照相机、MGC500(TeraRecon Inc.)获得。在使用99mTc(CO)3D(C8)L(MIP-1037)前,对动物(n=3)使用5分钟的赖诺普利(0.5mg/kg,i.v.)。5分钟后,对所有的动物(n=6)静脉注射5mCi/kg99mTc(CO)3D(C8)L(MIP-1037),5个1分钟平面腹部成像在注射10、30和60分钟后获得。
99mTc(CO)3D(C8)L(MIP-1037)吸收的解剖定位,利用小动物SPECT/CT也使用了带有小孔瞄准器的X-SPECT小动物扫描器(Gamma Medica,Inc.,Northridge,CA)。单独用99mTc(CO)3D(C8)L(MIP-1037)注射鼠或用赖诺普利(5分钟前/99mTc(CO)3D(C8)L(MIP-1037))注射治疗组(n=2/组)。用异荧烷/氧气混合物麻醉鼠。麻醉的动物固定在具体的设备上,以保证后面影像融合所需的完全不动。麻醉的程度通过用呼吸带测定呼吸频率进行监测。体温用直肠探测器控制,并用热电偶和加热的空气流保持在37℃。用生产者软件获得和重新构建SPECT数据。SPECT和CT数据的融合用标准方法处理。
如表I所示,每个铼络合物的抑制活性对照提纯的鼠肺ACE在体外进行评价,并随着链长(亚甲基间隔单元)直接变化;Re(CO)3D(C8)L(MIP-1037);IC50=3nM),Re(CO)3D(C5)L(MIP-1003);IC50=144nM),以及Re(CO)3D(C4)L(MIP-1039);IC50=1,146nM),和赖诺普利对比;IC50=4nM。有7个碳亚甲基间隔单元的类似物,MIP-103显示的活性等于母分子,赖诺普利。
表I:99mTc(CO)3D(Cx)L对提纯的鼠肺ACE的抑制活性
表II显示了99mTc(CO)3D(C8)L(MIP-1037)的鼠组织分布。在检查的所有组织中检测到不同水平的放射指示剂,并随着时间稳步减少。在肺部的吸收最大,具有高ACE表达的组织,注射10分钟后达到15.2%ID/g,保持3.93%ID/g2小时。通过肠内增加的放射性同位素示踪证实,间隔主要是通过肝胆路径。同时注射0.6mg/kg的非放射性标记的赖诺普利后,MIP-1037的吸收在肺部和其它组织中急剧减少,证明是特异性结合。鼠血浆的HPLC分析显示络合物在24小时内是稳定的,没有明显的分解。
表II:99mTc(CO)3D(C8)L(MIP-1037)的鼠组织分布
全体成像用于确定MIP-1037是否能用于非侵入性监测体内ACE活性。如上所述,用和不用赖诺普利预治疗的鼠用于体内成像规则。在每个动物的成像时间点,划出肺、肝脏、小肠和背部(软组织)的有用区域(ROIs)。每个ROI计数表达,ROIs在相同的时间点正常化为背景。图9显示了注射MIP-1037后10分钟获得的体内腹部全体平面图像。注射10分钟后的起始对照图像显示了肺、肝、小肠和膀胱中放射指示剂的吸收,该吸收能通过赖诺普利预治疗阻断。
此外,小动物SPECT/CT(Gamma Medica,Inc.,Northridge,CA)的成像研究定义了放射指示剂的解剖定位。和整体平面成像规则类似,鼠接受MIP-1037,有和没有上述的赖诺普利预治疗。如图10所示,赖诺普利预治疗阻断了突出的肺活性,其表明MIP-1037和组织(肺)ACE在体内的特异性结合。当对比对照组和预治疗组的图像时,MIP-1037在肺里的吸收在经过观察期60分钟(所有的时间点)大大降低了,如同ROIs计数的一样。肺内放射指示剂的吸收几乎在注射后60分钟消失。此外,MIP-1037吸收的大幅降低也在膀胱的10、30和60分钟时发现,以及在小肠的30和60分钟时发现。肝吸收是短暂的,从该器官清洗非常快,注射后的60分钟时几乎所有的放射活性消失在肠内。
带有多个亚甲基基团的D(Cx)L配位体用于形成M(CO)3 +络合物。最有功效的化合物M(CO)3D(C8)L在体内用99m-Tc测试。组织分布研究表明在含有ACE表达的器官中有高吸收,如肺。用赖诺普利预治疗的研究表明该化合物事实上是ACE特异性的。平面照相机成像和μSPECT/CT成像证实了体内的结果。与此对比,高亲和性Tc-99m标记的ACE抑制剂设计有和赖诺普利类似的功效。生物分布、药理学阻断研究和图像分析证实体内ACE的具体作用。该试剂能用于监测相关疾病状态的ACE调节。
上面对本发明进行了说明,并通过说明书和优选实施例进行了详细说明。对于本领域普通技术人员来说,不限于优选实施例的其它实施例也包含在本发明的范围内。相反,本发明的范围和下属权利要求书所表述的范围一致。
Claims (43)
1、一种包含偶联到放射性药物部分或光学成像部分的肽酶结合部分的化合物。
2、权利要求1所述的化合物,其中所述的放射性药物部分为放射成像部分、放射治疗部分,或二者。
3、权利要求1所述的化合物,其中所述的肽酶结合部分选自外肽酶或内肽酶抑制剂。
4、权利要求1所述的化合物,其中所述的肽酶结合部分包含羧肽酶结合部分,其中依次选自羧肽酶A1、羧肽酶A2、羧肽酶B、柱状细胞羧肽酶A、羧肽酶D、羧肽酶E、羧肽酶M、羧肽酶N或羧肽酶Z的抑制剂。
5、权利要求4所述的化合物,其中所述的肽酶结合部分包含ACE结合部分。
6、权利要求5所述的化合物,其中所述的ACE结合部分选自:阿拉普利、苯那普利、卡托普利、西罗普利、西拉普利、地拉普利、依那普利、依那普利拉、福辛普利、米卡普利、赖诺普利、莫西普利、莫维普利、平托普利、培哚普利、奎那普利、雷米普利、伦唑普利、螺普利、盐酸替莫普利、群多普利或左芬普利。
7、权利要求1所述的化合物,其中所述的放射成像部分包含放射性核种螯合物。
8、权利要求7所述的化合物,其中所述的放射性核种选自锝或铼。
9、权利要求8所述的化合物,其中所述的放射性核种选自锝-99m、铼-186或铼-188。
10、权利要求1所述的化合物,其中所述的放射成像部分包含(锝-99m)Tc(CO)3或(铼-186/188)Re(CO)3螯合物。
11、权利要求5所述的化合物,其中所述的ACE结合部分,和血清ACE相比,更大程度上抑制组织ACE。
12、权利要求5所述的化合物,其中ACE的IC50抑制小于20nM。
13、权利要求1所述的化合物,其中所述的肽酶结合部分和光学成像部分通过氨基化合物、酯、胺或醚键偶联。
14、一种成像哺乳动物的一个或多个器官或组织或二者的方法,该方法包括:给哺乳动物施用有效量的一种化合物,该化合物包含偶联到放射成像部分或光学成像部分的肽酶结合部分;以及获得哺乳动物的一个或多个器官或组织或二者的图像。
15、权利要求14所述的方法,其中所述的化合物静脉注射施用。
16、权利要求14所述的方法,其中所述的化合物选自冷的铼标记或锝-99m标记的D(C4)L(1)、D(C5)L(2)、D(C6)L(3)或D(C8)L(4)。
17、权利要求14所述的方法,其中所述的一个或多个器官或组织或二者包括肺组织。
18、权利要求14所述的方法,其中所述的一个或多个器官或组织或二者包括肾组织。
19、权利要求14所述的方法,其中所述的一个或多个器官或组织或二者包括心脏组织。
20、权利要求14所述的方法,其中所述的一个或多个器官或组织或二者包括肿瘤组织。
21、权利要求14所述的方法,其中所述的一个或多个器官或组织或二者包括易受伤的斑块的情况。
22、权利要求14所述的方法,其中所述的一个或多个器官或组织或二者包括动脉粥样化的情况。
23、权利要求14所述的方法,其中所述的一个或多个器官或组织或二者包括炎症的情况。
24、一种试剂盒,该试剂盒包括:(i)包含偶联到金属螯合物部分的肽酶结合部分的化合物;以及(ii)放射性核种。
25、权利要求24所述的试剂盒,其中所述的放射性核种选自锝-99m、铼-186或铼-188,或其组合。
26、一种分级和哺乳动物一个或多个器官或组织或二者相关的病理学症状的方法,该方法包括:(i)给哺乳动物施用有效量的一种化合物,该化合物包含偶联到放射成像部分的肽酶结合部分,(ii)获得所述哺乳动物一个或多个器官或组织或二者的图像,(iii)由所述图像确定存在于所述哺乳动物一个或多个器官或组织或二者的肽酶,以及(iv)利用确定的量和对照的量达到病理学症状的阶段。
27、权利要求26所述的方法,其中所述的病理学症状选自心力衰竭、心肌症、肺病、肾功能不全、肾衰竭、炎症、动脉硬化、易损动脉斑块或肿瘤。
28、一种监测哺乳动物响应治疗和一个或多个器官或组织或二者相关的病理学症状的方法,该方法包括:(i)给哺乳动物施用有效量的一种化合物,该化合物包含偶联到放射成像部分的肽酶结合部分,(ii)获得哺乳动物一个或多个器官或组织或二者的图像,(iii)由所述图像确定存在于所述哺乳动物一个或多个器官或组织或二者,以及(iv)利用确定的量和对照的量以精确计量哺乳动物对治疗的响应,如果有。
29、权利要求26所述的方法,其中所述的对照量是组里的平均量。
30、权利要求26所述的方法,其中所述的对照量是所述哺乳动物的一个或多个器官的基线量。
31、权利要求28所述的方法,其中所述的对照量是组里的平均量。
32、权利要求28所述的方法,其中所述的对照量是所述哺乳动物的一个或多个器官的基线量。
33、一种在哺乳动物一个或多个器官或组织或二者中定量肽酶表达的方法,该方法包括:给哺乳动物施用有效量的一种化合物,该化合物包含偶联到放射成像部分的肽酶结合部分;以及获得哺乳动物的一个或多个器官或组织或二者的图像;由所述图像和一系列标准图像在哺乳动物一个或多个器官或组织或二者中定量肽酶表达。
34、一种对所需哺乳动物进行放射疗法的方法,该方法包括给哺乳动物施用有效量的一种化合物,该化合物包含偶联到放射治疗部分的肽酶结合部分。
35、权利要求34所述的方法,其中所述的化合物是静脉注射施用。
36、权利要求34所述的方法,其中所述的哺乳动物患有肿瘤症状。
37、一种具有下式的化合物:
(PBM)n-(LIN)-(CHE)m
其中,
PBM含有肽酶结合部分,
n为1、2或3,
LIN为共价键,-CH2-、-NH-,或碳原子为2-20的线性或支链,并且可选择的结合到或包含在链中的是包括氨基、氧、硫、羰基、尿素的1-6个杂原子,或为氨基化合物、芳香环、环形脂肪环、杂芳环,或杂环脂肪环,以及共价连接到螯合部分,该螯合部分可以是能够结合放射性核种的单配位基、二配位基或多配位基配位体,以及
m为1、2或3。
38、权利要求37所述的化合物,其中所述的肽酶结合部分为羧肽酶A1、羧肽酶A2、羧肽酶B、柱状细胞羧肽酶A、羧肽酶D、羧肽酶E、羧肽酶M、羧肽酶N或羧肽酶Z的抑制剂。
39、权利要求38所述的化合物,其中所述的肽酶结合部分为阿拉普利、苯那普利、卡托普利、西罗普利、西拉普利、地拉普利、依那普利、依那普利拉、福辛普利、米卡普利、赖诺普利、莫西普利、莫维普利、平托普利、培哚普利、奎那普利、雷米普利、伦唑普利、螺普利、盐酸替莫普利、群多普利或左芬普利。
40、权利要求37所述的化合物,其中所述的连接剂为2-15个原子的链,其中1-6个原子的链为氨基、氧、硫、羰基、尿素或氨基化合物,并且链中剩下的原子为碳。
41、权利要求40所述的化合物,其中所述的连接剂包含赖氨酸或赖氨酸类似物,如图6或图7所示的赖氨酸类似物。
42、权利要求37所述的化合物,其中所述的放射性核种为锝或铼。
43、权利要求37所述的化合物,其中所述的CHE部分为吡啶甲撑基胺、喹啉亚甲基胺、异喹啉胺、吡啶-2-基甲氨基乙酸、异喹啉基-3-基甲氨基乙酸、噻唑-2-基甲基胺和噻唑-2-基甲氨基乙酸或下述结构的螯合物,其中显示和锝连接:
R8选自O、H、OH烷氧基或O-烷基,
R9为药学上可接受的杂环,如含有1-2个氮、氧或硫原子的5或6元环,
R8选自O、H、OH烷氧基或O-烷基,
R9为药学上可接受的杂环,如含有1-2个氮、氧或硫原子的5或6元环,
R10和R11分别单独为氢、烷基或取代的烷基;
R12选自烷基、芳基或杂环;
R13、R14、R15、R16、R17、R18、R19、R20单独为氢或甲基。
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CN103006632A (zh) * | 2012-12-31 | 2013-04-03 | 苏州大学 | 化合物Clik148在制备治疗脑血管疾病的药物中的应用 |
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WO2010036814A1 (en) * | 2008-09-25 | 2010-04-01 | Molecular Insight Pharmaceuticals, Inc. | Selective seprase inhibitors |
WO2010065899A2 (en) | 2008-12-05 | 2010-06-10 | Molecular Insight Pharmaceuticals, Inc. | Technetium-and rhenium-bis(heteroaryl)complexes and methods of use thereof |
WO2010065902A2 (en) * | 2008-12-05 | 2010-06-10 | Molecular Insight Pharmaceuticals, Inc. | Technetium- and rhenium-bis(heteroaryl) complexes and methods of use thereof for inhibiting psma |
US8211402B2 (en) | 2008-12-05 | 2012-07-03 | Molecular Insight Pharmaceuticals, Inc. | CA-IX specific radiopharmaceuticals for the treatment and imaging of cancer |
US8465725B2 (en) | 2009-06-15 | 2013-06-18 | Molecular Insight Pharmaceuticlas, Inc. | Process for production of heterodimers of glutamic acid |
JP2014515031A (ja) * | 2011-05-12 | 2014-06-26 | メタロファーム エルエルシー | 薬理学的特性が向上した金属製剤ならびにその製造方法および使用 |
US10449260B2 (en) | 2011-07-08 | 2019-10-22 | Theodosia Maina-Nock | Enhanced in vivo targeting of radiolabelled peptides with the means of enzyme inhibitors |
AU2013207486A1 (en) | 2012-01-06 | 2014-08-21 | Molecular Insight Pharmaceuticals | Metal complexes of poly(carboxyl)amine-containing ligands having an affinity for carbonic anhydrase IX |
EP2894477A4 (en) * | 2012-09-05 | 2016-07-20 | Wako Pure Chem Ind Ltd | METHOD FOR DETECTION OF BREAST CANCER |
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US6589503B1 (en) * | 1998-06-20 | 2003-07-08 | Washington University | Membrane-permeant peptide complexes for medical imaging, diagnostics, and pharmaceutical therapy |
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CN103006632B (zh) * | 2012-12-31 | 2015-04-22 | 苏州大学 | 化合物Clik148在制备治疗脑血管疾病的药物中的应用 |
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