CN1351496A - 包含调节细胞容量的人激酶h－sgk的抑制剂的药物 - Google Patents

包含调节细胞容量的人激酶h－sgk的抑制剂的药物 Download PDF

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CN1351496A
CN1351496A CN00807959A CN00807959A CN1351496A CN 1351496 A CN1351496 A CN 1351496A CN 00807959 A CN00807959 A CN 00807959A CN 00807959 A CN00807959 A CN 00807959A CN 1351496 A CN1351496 A CN 1351496A
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弗洛里安·朗
西格菲尔德·沃尔德杰
卡斯藤·瓦格纳
斯蒂芬·布罗尔
卡林·科林格尔
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Abstract

本发明涉及包含调节细胞容量的人激酶h－sgk的抑制剂或激活剂的药物。这类药物适用于治疗其中h－sgk的表达增加或减少的病理状态。

Description

包含调节细胞容量的人激酶h-sgk的抑制剂的药物
本发明涉及包含调节细胞容量的人激酶h-sgk的抑制剂或激活剂的药物。这类药物适用于治疗其中h-sgk的表达增加或减少的病理状态。EP-0 861 896已描述了h-sgk及其制备方法，该文的内容也特意引入以构成本说明书的一部分。
术语的定义：
h-sgk：人血清和糖皮质素依赖性激酶(丝氨酸/苏氨酸激酶)
ENaC：上皮Na+通道
MDEG：哺乳动物退化蛋白(Waldmann，R.，Lazdunski，M.(1998)《神经生物学流行观点》8：418-424)；同义词是“BNC”(脑Na+通道)
TGFβ1：肿瘤生长因子β1
NKCC：Na+，K+，2Cl-协同转运蛋白
HEPES：[4-(2-羟乙基)哌嗪基]乙磺酸
SEM：平均标准误差
反式显性抑制激酶：通过突变修饰的h-sgk：127位上的赖氨酸已被精氨酸取代(K127R)；突变位于催化区中并抑制激酶的催化功能。
糖尿病、动脉硬化、早老性痴呆、肝硬化、节段性回肠炎、纤维化胰腺炎、肺纤维变性和慢性支气管炎中常见h-sgk的表达增加。h-sgk的产生增加可以用TGFβ1对表达的刺激来解释(图1)。纤维变性疾病是由基质蛋白的形成增加和分解减少引起的。二者都是TGFβ1的作用。成纤维细胞中基质蛋白表达的增加可以通过用呋塞米抑制NKCC得以抑制(图2)。迄今仍不清楚h-sgk表达的增加仅是结果还是疾病的原因。
现在出人意料的发现证明h-sgk激活Na+，K+，2Cl-协同转运(图3)。由此可以得出结论：h-sgk对NKCC的刺激诱导纤维变性。除了Na+，K+，2Cl-协同转运外，h-sgk还激活ENaC(图4和5)和MDEG。
h-sgk对ENaC的刺激作用可以用激酶抑制剂诸如象星形孢菌素(Sigma，D-82041 Deisenhofen)或白屈菜红(Chelerythrin)(Sigma，loc.cit)加以抑制(图4)。另外，h-sgk对ENaC的作用可以用反式显性抑制激酶抑制(图5)。h-sgk的抑制剂诸如星形孢菌素、白屈菜红或其他激酶抑制剂因此可用于治疗上面所提到的疾病。一般来说，适合于此目的的是所有已知的激酶抑制剂。在许多情况下，激酶抑制剂也可从商业上获得，例如从Calbiochem-NovabiochemGmbH，Listweg 1，D-65812 Bad Soden购得(参见“1998年总商品目录”)。其他激酶抑制剂可以从技术人员已知的其他商业或非商业来源得到。
在癫痫发作中h-sgk的表达增加。我们已发现的功能数据显示该作用适于减少神经元的应激性，因为NKCC的激活导致细胞外K+浓度下降，接着发生超极化并因此抑制了神经元的活性。此外，MDEG的抑制会抑制神经元的应激性。因此，穿过血脑屏障的激酶激动剂可以成功地用于癫痫发作。相反，穿过血脑屏障的药物对激酶的抑制可能增加注意力和学习能力。此外，激酶激活剂已为技术人员知悉了很长时间，其中蛋白质激酶C激活剂是特别令人感兴趣的(参见：例如Calbiochem-Novabiochem 1998 General Catalog，loc.cit.)。其他激酶激活剂可以从技术人员已知的其他商业和非商业来源得到。
由于Na+，K+，2Cl-协同转运和Na+通道对肾的Na+吸收是决定性的，且肾Na+吸收的增加伴随高血压，因此必须假定激酶的表达增加导致高血压，而激酶的表达减少导致低血压。
本发明因此还涉及h-sgk的抑制剂在生产用于治疗糖尿病、动脉硬化、早老性痴呆、肝硬化、节段性回肠炎、纤维化胰腺炎、肺纤维变性、慢性支气管炎、放射性纤维化、硬皮病、囊纤维变性和其他纤维变性疾病的药物、以及用于治疗本质性高血压的药物中的用途。包含h-sgk的抑制剂或激活剂的药物另外还可用于调节神经元的应激性。特别有利的是使用抑制剂星形孢菌素或白屈菜红及它们的类似物。
结果
糖尿病性肾：
h-sgk在正常肾脏中的表达只是很低的。肾小球、后近端和远端小管中的一些细胞显示出清楚的h-sgk表达。与此对照，具有大量h-sgk表达的细胞积聚在糖尿病性肾中。
动脉硬化：
大量表达h-sgk的细胞常见于动脉硬化脉管的管壁中。
早老性痴呆：
在正常的脑中只有零星的表达h-sgk的细胞。这些细胞大概是少突神经胶质细胞。表达h-sgk的细胞的量在早老性痴呆患者的脑中明显增加。
肝硬化：
在正常的肝脏中只有铜细胞表达h-sgk。但是，在肝硬化中，组织中密布表达h-sgk的细胞。
节段性回肠炎：
在正常的肠组织中，h-sgk只在肠细胞中表达。但是在节段性回肠炎中，结缔组织中也发现了激酶。
纤维化胰腺炎：
在正常的胰腺中，h-sgk见于腺泡细胞和管细胞。在胰腺管周围可见偶见表达h-sgk的单核细胞。在纤维化胰腺炎中激酶的表达有显著的增加。
肺纤维变性和慢性支气管炎：
在肺纤维变性和慢性支气管炎中观察到h-sgk的大量表达。
TGFβ1对h-sgk表达的刺激：
h-sgk的表达受到TGFβ1的刺激(图1)。既然TGFβ1在纤维化/发炎的组织中产生，这一发现就解释了在发炎的组织中h-sgk的表达增加的原因。
TGFβ1刺激基质蛋白双糖链蛋白聚糖的表达，一种受到NKCC抑制剂呋塞米抑制的作用：
TGFβ1刺激双糖链蛋白聚糖的表达。在NKCC抑制剂呋塞米的存在下，TGFβ1对双糖链蛋白聚糖表达的作用完全被抑制。因此NKCC的活化是TGFβ1的纤维化作用的先决条件(图2)。
h-sgk对NKCC的刺激：
激酶在纤维化组织中表达增加的重要性可能是多方面的，与纤维变性没有因果联系。但是，用双电极电压夹钳进行的实验显示NKCC的活性受到h-sgk的极大刺激(图3)。鉴于双糖链蛋白聚糖合成的呋塞米敏感性，这一发现明确地证明了h-sgk在纤维变性中的因果性作用。
h-sgk对ENaC的刺激：
这种作用可以受到激酶抑制剂星形孢菌素和白屈菜红的抑制。如图4所示，通过与h-sgk共表达而使得通过ENaC的流量大量增加。因此激酶刺激ENaC。激酶抑制剂星形孢菌素和白屈菜红能完全抑制h-sgk对ENaC的活化。
h-sgk对上皮ENaC的刺激可以通过反式显性抑制激酶h-sgk的共表达逆转：
如图5所示，h-sgk共表达对ENaC介导的Na+流量的刺激作用可以通过反式显性抑制激酶的共表达得以抑制。这种反式显性抑制激酶(对照“术语的定义”)的催化单元上进行的修饰使得它能不再表现出其功能。但是，由于它能结合底物，因此能置换活性激酶并由此抑制其作用。反式显性抑制激酶不仅抑制外源h-sgk导致的ENaC活性的增加，而且明显抑制内源h-sgk引起的刺激。
MDEG通过与h-sgk的共表达而完全阻断：
如图6所示，MDEG在卵母细胞中的表达导致了强Na+流量，其通过降低细胞外pH而激活。该通道完全被与h-sgk的共表达阻断。由此必定得出结论：h-sgk抑制神经元应激性。
实施例：
实施例1：原位杂交
将从正常的胰腺、肝、血管、脑、肺、肾和肠得到的组织、以及患有糖尿病性肾病、动脉硬化、早老性痴呆、肝硬化、节段性回肠炎、纤维化胰腺炎和肺纤维变性的组织在石蜡中在4％低聚甲醛/0.1M磷酸钠缓冲液(pH7.2)中包埋4小时。将组织切片脱蜡并如以前所述进行杂交(Kandolf，R.，D.Ameis，P.Kirschner，A.Canu，P.H.Hofschneider，《美国国家科学院院报》84：6272-6276，1987年；Hohenadl，C.，K.Klingel，J.Mertsching，P.H.Hofschneider，R.Kandolf.，《分子细胞探针》5：11-20，1991年；Klingel，K.，C.Hohenadl，A.Canu，M.Albrecht，M.Seemann，G.Mall，R.Kandolf，《美国国家科学院院报》89：314-318，1992年)。
杂交混合物或者含有35S标记的编码h-sgk的有义RNA，或者含有35S标记的与最后提及的RNA互补的反义RNA(各500ng/ml)，它们都存在于10mM Tris-HCl，pH7.4；50％(vol/vol)去离子甲酰胺；600mMNaCl；1mM EDTA；0.2％聚乙烯吡咯烷酮；0.02％菲可；0.05％小牛血清白蛋白；10％葡聚糖硫酸酯；10mM二硫苏糖醇；200μg/ml变性的超声处理过的鲑精子DNA和100μg/ml兔肝tRNA。
与RNA探针的杂交在42℃下进行18小时。玻片如(Hohenadl等，1991年；Klingel等，1992年)所述洗涤，然后在2x标准柠檬酸钠中在55℃下培养1小时。未杂交的单链RNA探针用存在于10mMTris-HCl，pH8.0/0.5M NaCl中的RNA酶A(20μg/ml)在37℃下消化30分钟。然后组织样品放射自显影3周(Klingel等，1992年)并用苏木精/曙红染色。
实施例2：双糖链蛋白聚糖和h-sgk的转录调节
细胞在添加了10％(vol/vol)胎牛血清(FCS)的RPMI/5％CO2/10mM葡萄糖中在37℃、pH7.4下培养。细胞生长至90％融合，然后在TRIZOL(GIBCO/BRL)中匀化(每份样品约0.4×106)。按照制造商的指示制备总RNA。Northern印迹的分级分离利用在2.4mol/l甲醛的存在下通过带有15或20μg总RNA和独立的对照的10g/l琼脂糖凝胶电泳进行。RNA通过真空(Appligene Oncor Trans DNA Express VacuumBlotter，Appligene，Heidelberg，Germany)转移到带正电荷的尼龙膜(Boehringer Mannheim，Germany)上，在紫外线(UVStratalinker 2400，Stratagene，Heidelberg，Germany)下交联。杂交用DIG-Easy-Hyb(Boehringer Mannheim)以25μl/l的探针浓度在50℃下进行过夜。用地高辛配基(DIG)标记的探针如早先的详细描述(Waldegger等(1997)PNAS 94：4440-4445)通过PCR生产。至于放射自显影法，让滤器暴露于X射线膜(Kodak)平均5分钟。
实施例3：双电极电压夹钳和示踪流实验
有爪蟾蜍的解剖以及卵母细胞的获得和处理已在早先作了详细描述(Busch等，1992年)。卵母细胞各自注射1ng NKCC、ENaC或MDEG的cRNA，同时注射或不注射h-sgk。注射后2-8天就可进行双电极电压和流量夹钳实验。被呋塞米抑制的通过NKCC的Na+流入利用摄取到卵母细胞中的22Na+摄取测量，其用闪烁计数器确定。Na+流量(ENaC)在10Hz过滤并用笔记录器记录。实验通常在cRNA注射后的第二天进行。浴溶液含有：96mM NaCl，2mM Kcl，1.8mM CaCl2，1mM MgCl2和5mM HEPES，pH7.5，支持电位为-50mVY。所有实验中pH通过用HCl或NaOH滴定来调节。浴液的流动速率设定为20ml/分钟，它能确保在测量室中在10-15秒内完全改变溶液。所有数据以算术平均值±SEM的形式给出。
附例说明：
图1：TGFβ1对h-sgk表达的刺激：
h-sgk的表达受TGFβ1的刺激。显示了0.5到6小时后TGFβ1的作用(上图)。佛波酯PDD(4-α-佛波醇12，13-二癸酸酯；刺激蛋白激酶C)和Ca++离子载体离子霉素(Sigma，lot.cit；增加细胞内Ca++浓度)同样刺激h-sgk表达(下图)。
图2：TGFβ1对双糖链蛋白聚糖表达的刺激：
    双糖链蛋白聚糖(B)的表达受细胞渗透膨胀(hypo＝h，左上图)和TGFβ1(右上图)的刺激。TGFβ1对双糖链蛋白聚糖表达的作用在NKCC抑制剂布美他尼(b)(对照＝c)的存在下几乎完全被抑制。
图3：h-sgk对NKCC的刺激：
    22Na+在表达NKCC的卵母细胞中的能被呋塞米抑制的摄取〔摄取(nmol/20分钟/卵母细胞)＝u〕受到h-sgk的极大刺激。注射了NKCC的卵母细胞没有显示出比未经注射的卵母细胞(n.i.)更高的Na+流入。这种Na+流入没有被NKCC抑制剂呋塞米(＝F)抑制(上图)。单独的h-sgk的表达没有导致对Na+流入的刺激。h-sgk与NKCC的共表达导致Na+流入大量增加，这种增加完全被呋塞米抑制(下图)。
图4：h-sgk对ENaC的刺激：
    通过ENaC的流量(I)通过与h-sgk的共表达而大大增加了。卵母细胞用激酶抑制剂星形孢菌素(S)或白屈菜红(C)处理抑制了h-sgk对Na+通道的活化。
图5：h-sgk对ENaC的刺激可以通过反式显性抑制激酶的共表达逆转：
    同时表达ENaC和h-sgk的卵母细胞显示出比只表达ENaC的卵母细胞大得多的流量(I)。反式显性抑制激酶的共表达抑制了h-sgk对ENaC的刺激。
图6：h-sgk对MDEG的抑制：
通过MDEG的流量(I)在培养持续过程中增加〔天(T)1-4〕。该流量完全被与h-sgk的共表达抑制(峰值＝p；稳定水平＝pl)。

Claims (9)

1、包含调节细胞容量的人激酶h-sgk的抑制剂的药物。
2、如权利要求1所述的药物，其中抑制剂是星形孢菌素或白屈菜红。
3、包含调节细胞容量的人激酶h-sgk的激活剂的药物。
4、如权利要求3所述的药物，其中激活剂能穿过血脑屏障。
5、调节细胞容量的人激酶h-sgk的抑制剂、特别是星形孢菌素或白屈菜红在生产用于治疗纤维变性疾病的药物中的用途。
6、如权利要求5所述的用途，其中疾病包括下列一种或多种：动脉硬化、早老性痴呆、肝硬化、节段性回肠炎、纤维化胰腺炎、肺纤维变性、慢性支气管炎、放射性纤维化、硬皮病或囊纤维变性。
7、调节细胞容量的人激酶h-sgk的抑制剂、特别是星形孢菌素或白屈菜红在生产用于治疗糖尿病或原发性高血压的药物中的用途。
8、调节细胞容量的人激酶h-sgk的激活剂在生产用于治疗癫痫的药物中的用途。
9、如权利要求8所述的用途，其中激活剂能穿过血脑屏障。
CN00807959A 1999-04-20 2000-04-19 包含调节细胞容量的人激酶h－sgk的抑制剂的药物 Pending CN1351496A (zh)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100406570C (zh) * 2002-06-04 2008-07-30 弗洛里安·朗 用作诊断和治疗靶标的Sgk和Nedd
CN100529101C (zh) * 2003-03-03 2009-08-19 弗洛里安·朗 用作诊断和治疗靶的sgk1
CN107875153A (zh) * 2017-11-16 2018-04-06 上海壹志医药科技有限公司 去甲白屈菜红碱的药物用途

Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10042137A1 (de) * 2000-08-28 2002-03-14 Florian Lang sgk2 und sgk3 als diagnostische und therapeutische Targets
DE10113876A1 (de) * 2001-03-21 2002-09-26 Eberhard Karls Uni Medizinisch Quantitative diagnostische Analyse der Hypertonie
DE60233398D1 (de) * 2001-04-27 2009-10-01 Cold Spring Harbor Lab Linderung der gedächtnisdefizite und gedächtniskomponenten von psychiatrischen funktionsstörungen durch veränderung der atypischen pkm-aktivität
DE10149393A1 (de) * 2001-09-28 2003-04-24 Florian Lang sgk1 als diagnostisches und therapeutisches target
DE10305212A1 (de) * 2003-02-07 2004-08-19 Florian Prof. Dr.med. Lang Verwendung der sgk-Genfamilie zur Diagnose und zur Therapie von Katarakt und Glaukom
WO2004084889A1 (en) * 2003-03-28 2004-10-07 Pfizer Inc. Use of protein kinase c inhibitor for suppressing sustained slow postsynaptic excitation (sspe) of enteric neurons
DE10346913A1 (de) 2003-10-09 2005-05-04 Merck Patent Gmbh Acylhydrazonderivate
WO2005084702A1 (ja) * 2004-03-02 2005-09-15 Hokkaido Technology Licensing Office Co., Ltd. 臓器線維症予防・治療剤
WO2005094796A2 (en) * 2004-03-11 2005-10-13 Merck Patent Gmbh Methods for interfering with fibrosis
AU2005229496A1 (en) * 2004-03-11 2005-10-13 Merck Patent Gmbh Methods for modulating glutamate receptors for treating neuropsychiatric disorders comprising the use of modulators of serum and glucocorticoid inducible kinases
WO2005106491A2 (en) * 2004-04-30 2005-11-10 Bayer Healthcare Ag Diagnostics and therapeutics for diseases associated with serum/glucocorticoid regulated kinase 1 (sgk1)
WO2005118832A2 (en) * 2004-06-01 2005-12-15 Bayer Healthcare Ag Diagnostics and therapeutics for diseases associated with serum/glucocorticoid regulated kinase-like protein (sgkl)
DE102004030987A1 (de) * 2004-06-26 2006-01-12 Merck Patent Gmbh Ortho-substituierte (3-Hydroxyphenyl)-essigsäure-benzyliden-hydrazide
MX2007001155A (es) * 2004-07-29 2007-08-14 Creabilis Therapeutics Spa Uso de inhibidores de k-252a y de quinasa para la prevencion o el tratamiento de patologias asociadas con hmgb1.
DE102005001053A1 (de) * 2005-01-07 2006-07-20 Merck Patent Gmbh Quadratsäurederivate
DE102005015255A1 (de) * 2005-04-04 2006-10-05 Merck Patent Gmbh Acylhydrazide
DE102005035742A1 (de) * 2005-07-29 2007-02-01 Merck Patent Gmbh Quadratsäurederivate II
DE102005039541A1 (de) * 2005-08-22 2007-03-22 Merck Patent Gmbh 3-Oxo-indazol-quadratsäurederivate
DE102007002717A1 (de) 2007-01-18 2008-07-24 Merck Patent Gmbh Heterocyclische Indazolderivate
DE102007022565A1 (de) 2007-05-14 2008-11-20 Merck Patent Gmbh Heterocyclische Indazolderivate
EP2014651A1 (en) * 2007-07-12 2009-01-14 Exonhit Therapeutics SA Compounds and methods for modulating Rho GTPases
DE102008010362A1 (de) 2008-02-18 2009-08-20 Florian Prof. Dr. Lang Sgk1 als therapeutisches und diagnostisches Target für virale Erkrankungen
DE102008010361A1 (de) 2008-02-18 2009-08-20 Merck Patent Gmbh sgk1-Inhibitoren zur Prophylaxe und/oder Therapie von viralen Erkrankungen und/oder Karzinomen
DE102008010363A1 (de) 2008-02-18 2009-08-20 Lang, Florian, Prof. Dr.med. Sgk1 als therapeutisches und diagnostisches Target für karzinomatöse Erkrankungen
DE102008029072A1 (de) * 2008-06-10 2009-12-17 Lang, Florian, Prof. Dr.med. Sgk3 als therapeutisches und diagnostisches Target für Alterserkrankungen
DE102008038222A1 (de) 2008-08-18 2010-02-25 Merck Patent Gmbh Indazol-5-carbonsäurehydrazid-derivate
DE102008038221A1 (de) 2008-08-18 2010-02-25 Merck Patent Gmbh 7-Azaindolderivate
DE102008038220A1 (de) 2008-08-18 2010-02-25 Merck Patent Gmbh Oxadiazolderivate
DE102008059133A1 (de) 2008-11-26 2010-05-27 Merck Patent Gmbh Difluorphenyl-diacylhydrazid-derivate
EP2637650A2 (en) 2010-11-10 2013-09-18 National Jewish Health Methods to test allergic conditions

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5373501A (en) * 1976-12-11 1978-06-30 Kitasato Inst Novel antibiotics amm2282 and process for preparing same
US5242397A (en) * 1989-06-20 1993-09-07 Cedars-Sinai Medical Center Catheter device and method of use for intramural delivery of protein kinase C and tyrosine protein kinase inhibitors to prevent restenosis after balloon angioplasty
US5137912A (en) * 1991-01-28 1992-08-11 National Science Council Of Republic Of China Chelerythrine inhibits platelet aggregation--a potential anti-aggregation drug
DE4217964A1 (de) * 1992-05-30 1993-12-02 Goedecke Ag Indolocarbazol-Imide und deren Verwendung
GB9325395D0 (en) * 1993-12-11 1994-02-16 Ciba Geigy Ag Compositions
US5874464A (en) * 1995-01-13 1999-02-23 The United States Of America As Represented By The Department Of Health And Human Services Conformationally constrained diacylglycerol analogues
AU6888196A (en) * 1995-08-11 1997-03-12 Yale University Glycosylated indolocarbazole synthesis
ES2170390T3 (es) * 1996-05-30 2002-08-01 Aventis Pharma Inc Fluorenonas alquiloxiamino-substituidas y su uso como inhibidores de la proteina kinasa-c.
EP0887081B1 (en) * 1997-06-27 2003-04-23 Smithkline Beecham Corporation Human serum glucocorticoid regulated kinase, a target for chronic renal disease and diabetic nephropathy
EP0889127A1 (en) * 1997-07-01 1999-01-07 Smithkline Beecham Corporation Serine/threonine protein kinase (H-SGK2)
CO4940430A1 (es) * 1997-07-07 2000-07-24 Novartis Ag Compuestos policiclicos que contienen estaurosporina hidrogenada con propiedades farmacologicas convenientes y un efecto inhibidor sobre el crecimiento de las celulas tumorales

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100406570C (zh) * 2002-06-04 2008-07-30 弗洛里安·朗 用作诊断和治疗靶标的Sgk和Nedd
CN100529101C (zh) * 2003-03-03 2009-08-19 弗洛里安·朗 用作诊断和治疗靶的sgk1
CN107875153A (zh) * 2017-11-16 2018-04-06 上海壹志医药科技有限公司 去甲白屈菜红碱的药物用途

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