CN1351496A - Medicaments containing inhibitors of cell-volume regulated human kinase h-sgk - Google Patents

Medicaments containing inhibitors of cell-volume regulated human kinase h-sgk Download PDF

Info

Publication number
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
Authority
CN
China
Prior art keywords
sgk
cell
medicine
human kinase
volume
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN00807959A
Other languages
Chinese (zh)
Inventor
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
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CN1351496A publication Critical patent/CN1351496A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/005—Enzyme inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Diabetes (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Obesity (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Hospice & Palliative Care (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Dermatology (AREA)
  • Vascular Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to medicaments which contain inhibitors or activators of cell-volume regulated human kinase h-sgk. Medicaments of this type are suitable for treating conditions, in which an increased or reduced expression of h-sgk is identified.

Description

The medicine that comprises the inhibitor of the human kinase h-sgk that regulates cell-volume
The present invention relates to comprise the inhibitor of the human kinase h-sgk that regulates cell-volume or the medicine of activator.This class medicine is applicable to treats the pathological state that the wherein expression of h-sgk increases or reduces.EP-0 861 896 has described h-sgk and preparation method thereof, and the content of this article is also specially introduced to constitute the part of this description.
The definition of term:
H-sgk: human serum and glucocorticoid dependant kinase (serine/threonine kinase)
ENaC: epithelium Na +Passage
MDEG: mammal degenerin (Waldmann, R., Lazdunski, M. (1998) " neurobiology prevailing view " 8:418-424); Synonym is " BNC " (brain Na +Passage)
TGF β 1: tumorgrowthfactor- 1
NKCC:Na +, K +, 2Cl -Cotransporter
HEPES:[4-(2-ethoxy) piperazinyl] ethyl sulfonic acid
SEM: standard error of mean
Trans-dominant suppresses kinases: replaced (K127R) by arginine by the lysine on the h-sgk:127 position of sudden change modification; Sudden change is arranged in catalytic domain and suppresses kinase whose catalysis.
The expression of common h-sgk increases in diabetes, arteriosclerosis, presenile dementia, liver cirrhosis, Crohn disease, fibrosis pancreatitis, pnemnofibrosis and the chronic bronchitis.The generation increase of h-sgk can be used TGF β 1(Fig. 1) explained in the stimulation of expressing.Fibrotic conditions is to be increased and decomposed to reduce by forming of stromatin to cause.The two all is TGF β 1Effect.The increase of fibroblast mesostroma protein expression can be suppressed (Fig. 2) by suppressing NKCC with furosemide.Do not know still that so far the increase that h-sgk expresses only is the result or the reason of disease.
Present beat all discovery proof h-sgk activates Na +, K +, 2Cl -Co-transport (Fig. 3).Can reach a conclusion thus: h-sgk induces fibre modification to the stimulation of NKCC.Except Na +, K +, 2Cl -Outside the co-transport, h-sgk also activates ENaC (Figure 4 and 5) and MDEG.
H-sgk can be all as if (Sigma loc.cit) is suppressed (Fig. 4) for D-82041 DEISENHOFEN (Sigma, D-82041 Deisenhofen) or chelerythrine (Chelerythrin) with inhibitors of kinases to the stimulation of ENaC.In addition, h-sgk can suppress kinase inhibition (Fig. 5) with trans-dominant to the effect of ENaC.The disease that the inhibitor of h-sgk such as D-82041 DEISENHOFEN, chelerythrine or other inhibitors of kinases are mentioned above therefore can be used for treating.What in general, be suitable for this purpose is all known inhibitors of kinases.In many cases, inhibitors of kinases also can be from commercial acquisition, and for example from Calbiochem-NovabiochemGmbH, Listweg 1, and D-65812 Bad Soden buys (referring to " total goods catalogue in 1998 ").Other inhibitors of kinases can obtain from other commerce known to the skilled or non-commercial source.
The expression of h-sgk increases in epilepsy.The performance data that we have found shows that this effect is suitable for reducing neuronic irritability, because the activation of NKCC causes extracellular K +Hyperpolarization then takes place and has therefore suppressed neuronic activity in lowering of concentration.In addition, the inhibition of MDEG can suppress neuronic irritability.Therefore, the kinases agonist that passes blood brain barrier can be successfully used to epilepsy.On the contrary, the medicine that passes blood brain barrier may increase attention and learning capacity to kinase whose inhibition.In addition, the kinase activator agent known for a long time for the technical staff, and wherein protein kinase C activator is to make us interested (referring to Calbiochem-Novabiochem 1998 General Catalog for example, loc.cit.) especially.Other kinase activator agent can obtain from other commerce known to the skilled and non-commercial source.
Because Na +, K +, 2Cl -Co-transport and Na +Passage is to the Na of kidney +Absorption is conclusive, and kidney Na +Hypertension is followed in the increase that absorbs, and therefore must suppose that kinase whose expression increase causes hypertension, and kinase whose expression decreased causes hypotension.
The inhibitor that the present invention therefore also relates to h-sgk is used for the treatment of the medicine of diabetes, arteriosclerosis, presenile dementia, liver cirrhosis, Crohn disease, fibrosis pancreatitis, pnemnofibrosis, chronic bronchitis, radioactive fibrosis, scleroderma, cystic fibrosis and other fibrotic conditions and is used for the treatment of purposes in the medicine of essential hypertension in production.Comprise the inhibitor of h-sgk or the medicine of activator and also can be used for regulating neuronic irritability in addition.Particularly advantageous inhibitor D-82041 DEISENHOFEN or chelerythrine and their analog of being to use.
The result
The diabetic kidney:
The expression of h-sgk in normal kidney is just very low.Some cells in glomerule, back near-end and the distal tubule demonstrate clearly, and h-sgk expresses.In contrast, has the cells accumulation of a large amount of h-sgk expression in the diabetic kidney.
Arteriosclerosis:
The cell of great expression h-sgk is common in the tube wall of arteriosclerosis vascular.
Presenile dementia:
The cell that in normal brain, has only odd expression h-sgk.These cells the chances are oligodendroglia.The amount of expressing the cell of h-sgk obviously increases in presenile dementia patient's brain.
Liver cirrhosis:
In normal liver, has only copper cellular expression h-sgk.But, in liver cirrhosis, gather in the tissue and express the cell of h-sgk.
Crohn disease:
In normal intestinal tissue, h-sgk only expresses in enterocyte.But in Crohn disease, also found kinases in the connective tissue.
The fibrosis pancreatitis:
In normal pancreas, h-sgk sees acinous cell and solencyte.The mononuclear cell of visible accidental expression h-sgk around pancreatic duct.Kinase whose expression has significant increase in the fibrosis pancreatitis.
Pnemnofibrosis and chronic bronchitis:
In pnemnofibrosis and chronic bronchitis, observe the great expression of h-sgk.
TGF β 1Stimulation to the h-sgk expression:
The expression of h-sgk is subjected to TGF β 1Stimulation (Fig. 1).Since TGF is β 1Produce in the tissue of fibrosis/inflammation, the reason that the expression of h-sgk in the tissue of inflammation increases has just been explained in this discovery.
TGF β 1Stimulate the expression of stromatin disaccharidase catenin polysaccharide, a kind of effect that is subjected to the inhibition of NKCC inhibitor furosemide:
TGF β 1Stimulate the expression of disaccharidase catenin polysaccharide.In the presence of NKCC inhibitor furosemide, TGF β 1The effect that disaccharidase catenin polysaccharide is expressed is suppressed fully.Therefore the activation of NKCC is TGF β 1The prerequisite (Fig. 2) of fibrosis effect.
H-sgk is to the stimulation of NKCC:
Kinases is expressed the importance that increases in the fibrosis tissue may be many-sided, do not have causal connection with fibre modification.But the experiment of carrying out with bipolar electrode voltage clamp shows that the activity of NKCC is subjected to the very big stimulation (Fig. 3) of h-sgk.In view of the synthetic furosemide sensitivity of disaccharidase catenin polysaccharide, this discovery has proved the causality effect of h-sgk in fibre modification clearly.
H-sgk is to the stimulation of ENaC:
This effect can be subjected to the inhibition of inhibitors of kinases D-82041 DEISENHOFEN and chelerythrine.As shown in Figure 4, by making the flow by ENaC roll up with the h-sgk coexpression.Therefore kinases stimulates ENaC.Inhibitors of kinases D-82041 DEISENHOFEN and chelerythrine can suppress the activation of h-sgk to ENaC fully.
H-sgk can suppress the coexpression reverse of kinases h-sgk by trans-dominant to the stimulation of epithelium ENaC:
As shown in Figure 5, the h-sgk coexpression is to the Na of ENaC mediation +The stimulation of flow can suppress kinase whose coexpression by trans-dominant and be suppressed.The modification that this trans-dominant suppresses to carry out on the catalyst unit of kinases (contrast " definition of term ") makes it can no longer show its function.But, because therefore its energy bound substrates can also suppress its effect by the substitute activity kinases thus.Trans-dominant suppresses kinases and not only suppresses the active increase of ENaC that external source h-sgk causes, and obviously suppresses the stimulation that endogenous h-sgk causes.
MDEG is by blocking fully with the coexpression of h-sgk:
As shown in Figure 6, the expression of MDEG in oocyte caused strong Na +Flow, it activates by reducing external pH.This passage is blocked with the coexpression of h-sgk fully.Must reach a conclusion thus: h-sgk suppresses neuron irritability.
Embodiment:
Embodiment 1: in situ hybridization
The tissue that will obtain from normal pancreas, liver, blood vessel, brain, lung, kidney and intestinal and suffer from diabetic nephropathy, arteriosclerosis, presenile dementia, liver cirrhosis, Crohn disease, fibrosis pancreatitis and pnemnofibrosis be organized in the paraffin in 4% paraformaldehyde/0.1M sodium phosphate buffer (pH7.2) embedding 4 hours.(Kandolf, R., D.Ameis, P.Kirschner, A.Canu, P.H.Hofschneider, " institute of NAS newspaper " 84:6272-6276,1987 are also hybridized in the tissue slice dewaxing as mentioned previously; Hohenadl, C., K.Klingel, J.Mertsching, P.H.Hofschneider, R.Kandolf., " molecular cell probe " 5:11-20,1991; Klingel, K., C.Hohenadl, A.Canu, M.Albrecht, M.Seemann, G.Mall, R.Kandolf, " institute of NAS newspaper " 89:314-318,1992).
Hybridization mixture or contain the 35S labelling coding h-sgk adopted RNA arranged, perhaps contain the 35S labelling and the complementary antisense RNA of RNA that mention at last (each 500ng/ml), they all are present in 10mM Tris-HCl, pH7.4; 50% (vol/vol) deionized formamide; 600mMNaCl; 1mM EDTA; 0.2% polyvinylpyrrolidone; 0.02% phenanthrene can; 0.05% bSA; 10% dextran sulfate; The 10mM dithiothreitol, DTT; Salmon sperm DNA that the supersound process of 200 μ g/ml degeneration is crossed and 100 μ g/ml Hepar Leporis seu Oryctolagi tRNA.
Under 42 ℃, carried out 18 hours with the hybridization of rna probe.Slide is as (Hohenadl etc., 1991; Klingel etc., 1992) described washing, in 2x standard sodium citrate, cultivated 1 hour down then at 55 ℃.Za Jiao single stranded RNA probe is not with being present in 10mMTris-HCl, and the RNA enzyme A among the pH8.0/0.5M NaCl (20 μ g/ml) digested 30 minutes down at 37 ℃.3 weeks of tissue sample autoradiography (Klingel etc., 1992) are also with hematoxylin/eosin dyeing then.
Embodiment 2: the transcriptional regulatory of disaccharidase catenin polysaccharide and h-sgk
Cell is at the RPMI/5%CO that has added 10% (vol/vol) hyclone (FCS) 2Under 37 ℃, pH7.4, cultivate in/10mM the glucose.Cell grows to 90% and merges, then (the every duplicate samples about 0.4 * 10 of homogenize in TRIZOL (GIBCO/BRL) 6).Indication according to manufacturer prepares total RNA.The fractionated utilization of Northern trace is undertaken by the 10g/l agarose gel electrophoresis that has total RNA of 15 or 20 μ g and independently contrast in the presence of 2.4mol/l formaldehyde.RNA is by vacuum (Appligene Oncor Trans DNA Express VacuumBlotter, Appligene, Heidelberg, Germany) transfer to positively charged nylon membrane (Boehringer Mannheim, Germany) on, (UVStratalinker 2400, Stratagene at ultraviolet, Heidelberg, Germany) crosslinked down.Hybridization is spent the night under 50 ℃ with the concentration and probe concentration of 25 μ l/l with DIG-Easy-Hyb (Boehringer Mannheim).Produce by PCR with the probe of digoxigenin (DIG) labelling such as previous detailed description (Waldegger etc. (1997) PNAS 94:4440-4445).As for autoradiography, allow filter be exposed to X ray film (Kodak) average 5 minutes.
Embodiment 3: bipolar electrode voltage clamp and the experiment of spike stream
Detailed description (Busch etc., 1992) has been made in the dissection of xenopus laevis and the acquisition of oocyte and processing previously.Oocyte is injected the cRNA of 1ng NKCC, ENaC or MDEG separately, injects or do not inject h-sgk simultaneously.The injection back just can be carried out the experiment of bipolar electrode voltage and flow clamp in 2-8 days.The Na that passes through NKCC that is suppressed by furosemide +Flow into to utilize and absorb in the oocyte 22Na +Picked-up is measured, and it is determined with scintillation counter.Na +Flow (ENaC) filters and uses the pen register record at 10Hz.Experiment second day after the cRNA injection is usually carried out.Bath solution contains: 96mM NaCl, 2mM Kcl, 1.8mM CaCl 2, 1mM MgCl 2With 5mM HEPES, pH7.5, support current potential to be-50mVY.PH is by regulating with HCl or NaOH titration in all experiments.The flow rate of body lotion is set at 20ml/ minute, and it can guarantee to change solution in second fully at 10-15 in measuring chamber.All data provide with the form of arithmetic mean of instantaneous value ± SEM.
Attached example explanation:
Fig. 1: TGF β 1Stimulation to the h-sgk expression:
The expression of h-sgk is subjected to TGF β 1Stimulation.TGF β after having shown 0.5 to 6 hour 1Effect (last figure).Buddhist ripple ester PDD (4-α-phorbol 12,13-dicaprate; The stimulatory protein(SP) kinase c) and Ca ++Ionophore ionomycin (Sigma, lot.cit; Increase Ca in the cell ++Concentration) stimulate h-sgk to express (figure below) equally.
Fig. 2: TGF β 1Stimulation to the expression of disaccharidase catenin polysaccharide:
The expression of disaccharidase catenin polysaccharide (B) is subjected to Premeabilisation of cells expansion (hypo=h, the picture left above) and TGF β 1The stimulation of (top right plot).TGF β 1The NKCC inhibitor bumetanide (b) that acts on that disaccharidase catenin polysaccharide is expressed (almost completely is suppressed under the existence of contrast=c).
Fig. 3: h-sgk is to the stimulation of NKCC:
22Na +The very big stimulation that can be subjected to h-sgk in the oocyte of expressing NKCC by the picked-up (picked-up (nmol/20 minute/oocyte)=u) that furosemide suppresses.The oocyte of having injected NKCC does not demonstrate than the higher Na of oocyte (n.i.) without injection +Flow into.This Na +Flow into not by the (=F) inhibition (last figure) of NKCC inhibitor furosemide.The expression of independent h-sgk does not cause Na +The stimulation that flows into.The coexpression of h-sgk and NKCC causes Na +Inflow rolls up, and this increase is suppressed (figure below) by furosemide fully.
Fig. 4: h-sgk is to the stimulation of ENaC:
Flow (I) by ENaC is by having increased greatly with the coexpression of h-sgk.Oocyte is handled with inhibitors of kinases D-82041 DEISENHOFEN (S) or chelerythrine (C) and has been suppressed h-sgk to Na +The activation of passage.
Fig. 5: h-sgk can suppress kinase whose coexpression reverse by trans-dominant to the stimulation of ENaC:
The oocyte of expressing ENaC and h-sgk simultaneously demonstrates the flow more much bigger than the oocyte of only expressing ENaC (I).Trans-dominant suppresses kinase whose coexpression and has suppressed the stimulation of h-sgk to ENaC.
Fig. 6: h-sgk is to the inhibition of MDEG:
Flow (I) by MDEG increases (my god (T) 1-4) in cultivating time-continuing process.This flow is suppressed (peak value=p by the coexpression with h-sgk fully; Maintenance level=pl).

Claims (9)

1, the medicine that comprises the inhibitor of the human kinase h-sgk that regulates cell-volume.
2, medicine as claimed in claim 1, wherein inhibitor is D-82041 DEISENHOFEN or chelerythrine.
3, the medicine that comprises the activator of the human kinase h-sgk that regulates cell-volume.
4, medicine as claimed in claim 3, wherein activator can pass blood brain barrier.
5, regulate inhibitor, the particularly D-82041 DEISENHOFEN of human kinase h-sgk of cell-volume or chelerythrine and be used for the treatment of purposes in the medicine of fibrotic conditions in production.
6, purposes as claimed in claim 5, wherein disease comprise following one or more: arteriosclerosis, presenile dementia, liver cirrhosis, Crohn disease, fibrosis pancreatitis, pnemnofibrosis, chronic bronchitis, radioactive fibrosis, scleroderma or cystic fibrosis.
7, regulate inhibitor, the particularly D-82041 DEISENHOFEN of human kinase h-sgk of cell-volume or chelerythrine and be used for the treatment of purposes in the medicine of diabetes or essential hypertension in production.
8, the activator of regulating the human kinase h-sgk of cell-volume is used for the treatment of purposes in the medicine of epilepsy in production.
9, purposes as claimed in claim 8, wherein activator can pass blood brain barrier.
CN00807959A 1999-04-20 2000-04-19 Medicaments containing inhibitors of cell-volume regulated human kinase h-sgk Pending CN1351496A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19917990.5 1999-04-20
DE19917990A DE19917990A1 (en) 1999-04-20 1999-04-20 Medicament containing inhibitors of cell volume regulated human kinase h-sgk

Publications (1)

Publication Number Publication Date
CN1351496A true CN1351496A (en) 2002-05-29

Family

ID=7905297

Family Applications (1)

Application Number Title Priority Date Filing Date
CN00807959A Pending CN1351496A (en) 1999-04-20 2000-04-19 Medicaments containing inhibitors of cell-volume regulated human kinase h-sgk

Country Status (18)

Country Link
EP (1) EP1171131A1 (en)
JP (1) JP2002542196A (en)
KR (1) KR100718900B1 (en)
CN (1) CN1351496A (en)
AU (1) AU779941B2 (en)
BR (1) BR0009914A (en)
CA (1) CA2369078A1 (en)
CZ (1) CZ20013778A3 (en)
DE (1) DE19917990A1 (en)
HU (1) HUP0200819A3 (en)
MX (1) MXPA01010588A (en)
NO (1) NO20015054L (en)
PL (1) PL198427B1 (en)
RU (1) RU2288718C9 (en)
SK (1) SK14972001A3 (en)
UA (1) UA79066C2 (en)
WO (1) WO2000062781A1 (en)
ZA (1) ZA200108610B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100406570C (en) * 2002-06-04 2008-07-30 弗洛里安·朗 Sgk and Nedd used as diagnostic and therapeutic targets
CN107875153A (en) * 2017-11-16 2018-04-06 上海壹志医药科技有限公司 The medicinal usage of Des-N-methylchelerythrine

Families Citing this family (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10042137A1 (en) * 2000-08-28 2002-03-14 Florian Lang sgk2 and sgk3 as diagnostic and therapeutic targets
DE10113876A1 (en) * 2001-03-21 2002-09-26 Eberhard Karls Uni Medizinisch Quantitative diagnosis of genetically related hypertension, by correlating blood pressure with overexpression or modification of human sgk family proteins
WO2002087417A2 (en) * 2001-04-27 2002-11-07 Cold Spring Harbor Laboratory Alleviation of the memory deficits and memory components of psychiatric dysfunctions by altering atypical pkm activity
DE10149393A1 (en) * 2001-09-28 2003-04-24 Florian Lang Detecting the expression of serum and glucocorticoid-dependent kinase-1 (sgk1), for diagnosing coagulative diseases, diabetes, tumors, diabetes and autoimmune diseases, comprises using an antibody against sgk1
DE10305212A1 (en) * 2003-02-07 2004-08-19 Florian Prof. Dr.med. Lang Use of the sgk gene family for the diagnosis and therapy of cataracts and glaucoma
KR20110005747A (en) * 2003-03-03 2011-01-18 플로리안 랑 Sgk1 as diagnostic and therapeutic target
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 (en) 2003-10-09 2005-05-04 Merck Patent Gmbh acylhydrazone
WO2005084702A1 (en) * 2004-03-02 2005-09-15 Hokkaido Technology Licensing Office Co., Ltd. Agent for preventing and treating organ fibrosis
JP2007529423A (en) * 2004-03-11 2007-10-25 メルク　パテント　ゲゼルシャフト　ミット　ベシュレンクテル　ハフトング Methods for modulating glutamate receptors for the treatment of neuropsychiatric disorders, including the use of modulators of serum and glucocorticoid-inducible kinases
KR20070015149A (en) * 2004-03-11 2007-02-01 메르크 파텐트 게엠베하 Methods for interfering with fibrosis
US20090136920A1 (en) * 2004-04-30 2009-05-28 Stefan Golz 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 (en) * 2004-06-26 2006-01-12 Merck Patent Gmbh Ortho-substituted (3-hydroxyphenyl) -acetic acid benzylidene hydrazides
MX2007001155A (en) * 2004-07-29 2007-08-14 Creabilis Therapeutics Spa Methods, systems, and computer program products for providing presence gateway functionality in a telecommunications network.
DE102005001053A1 (en) * 2005-01-07 2006-07-20 Merck Patent Gmbh Square acid derivatives
DE102005015255A1 (en) 2005-04-04 2006-10-05 Merck Patent Gmbh New acylhydrazide compounds are signal transduction kinase inhibitor, useful for treating and/or preventing diseases, e.g. diabetes, adiposity, metabolic syndrome, cancer and tumor cells
DE102005035742A1 (en) * 2005-07-29 2007-02-01 Merck Patent Gmbh New cyclobut-3-ene-1,2-dione derivatives are kinase inhibitors useful for treating e.g. cancer, hypertension, diabetes, glaucoma and bacterial infections
DE102005039541A1 (en) * 2005-08-22 2007-03-22 Merck Patent Gmbh 3-oxo-indazol-square acid derivatives
DE102007002717A1 (en) 2007-01-18 2008-07-24 Merck Patent Gmbh Heterocyclic indazole derivatives
DE102007022565A1 (en) 2007-05-14 2008-11-20 Merck Patent Gmbh Heterocyclic indazole derivatives
EP2014651A1 (en) * 2007-07-12 2009-01-14 Exonhit Therapeutics SA Compounds and methods for modulating Rho GTPases
DE102008010362A1 (en) * 2008-02-18 2009-08-20 Florian Prof. Dr. Lang Sgk1 as a therapeutic and diagnostic target for viral diseases
DE102008010363A1 (en) 2008-02-18 2009-08-20 Lang, Florian, Prof. Dr.med. Sgk1 as a therapeutic and diagnostic target for carcinomatous diseases
DE102008010361A1 (en) 2008-02-18 2009-08-20 Merck Patent Gmbh sgk1 inhibitors for the prophylaxis and / or therapy of viral diseases and / or carcinomas
DE102008029072A1 (en) * 2008-06-10 2009-12-17 Lang, Florian, Prof. Dr.med. Substance, which inhibits serum and glucocorticoid dependent kinase 3, useful for the prophylaxis and/or treatment or diagnosis of age-related diseases e.g. arteriosclerosis, skin atrophy, myasthenia, infertility, stroke and kyphosis
DE102008038221A1 (en) 2008-08-18 2010-02-25 Merck Patent Gmbh 7-azaindole derivatives
DE102008038222A1 (en) 2008-08-18 2010-02-25 Merck Patent Gmbh Indazol-5-carboxylic acid derivatives
DE102008038220A1 (en) 2008-08-18 2010-02-25 Merck Patent Gmbh oxadiazole
DE102008059133A1 (en) 2008-11-26 2010-05-27 Merck Patent Gmbh Difluorophenyl diacylhydrazide derivatives
WO2012064981A2 (en) * 2010-11-10 2012-05-18 National Jewish Health Methods to test allergic conditions

Family Cites Families (10)

* 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
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
WO1997007081A2 (en) * 1995-08-11 1997-02-27 Yale University Glycosylated indolocarbazole synthesis
HUP9901621A3 (en) * 1996-05-30 2002-01-28 Aventis Pharmaceuticals Inc Br Protein kinase c inhibitory activity alkyloxyamino substituted fluorenone derivatives, use thereof, intermediates and preparation of the latters, pharmaceutical compositions containing these compounds
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 (en) * 1997-07-07 2000-07-24 Novartis Ag POLYCLIC COMPOUNDS CONTAINING HYDROGENATED STAUROSPORIN WITH CONVENIENT PHARMACOLOGICAL PROPERTIES AND AN INHIBITING EFFECT ON THE GROWTH OF TUMOR CELLS

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100406570C (en) * 2002-06-04 2008-07-30 弗洛里安·朗 Sgk and Nedd used as diagnostic and therapeutic targets
CN107875153A (en) * 2017-11-16 2018-04-06 上海壹志医药科技有限公司 The medicinal usage of Des-N-methylchelerythrine

Also Published As

Publication number Publication date
NO20015054D0 (en) 2001-10-17
PL198427B1 (en) 2008-06-30
ZA200108610B (en) 2002-01-02
UA79066C2 (en) 2007-05-25
RU2288718C9 (en) 2008-04-27
SK14972001A3 (en) 2002-06-04
WO2000062781A1 (en) 2000-10-26
JP2002542196A (en) 2002-12-10
EP1171131A1 (en) 2002-01-16
DE19917990A1 (en) 2000-11-02
CZ20013778A3 (en) 2002-06-12
AU779941B2 (en) 2005-02-17
MXPA01010588A (en) 2004-09-06
HUP0200819A3 (en) 2009-08-28
CA2369078A1 (en) 2000-10-26
KR20020012172A (en) 2002-02-15
AU4297200A (en) 2000-11-02
NO20015054L (en) 2001-12-14
HUP0200819A2 (en) 2002-07-29
BR0009914A (en) 2002-01-08
KR100718900B1 (en) 2007-05-17
RU2288718C2 (en) 2006-12-10
PL352547A1 (en) 2003-08-25

Similar Documents

Publication Publication Date Title
CN1351496A (en) Medicaments containing inhibitors of cell-volume regulated human kinase h-sgk
Goldhaber et al. Effects of TNF-alpha on [Ca2+] i and contractility in isolated adult rabbit ventricular myocytes
Lin et al. Opening a new time window for treatment of stroke by targeting HDAC2
Pei et al. NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism
Harris et al. Pathological responses of rat skeletal muscle to a single subcutaneous injection of a toxin isolated from the venom of the Australian tiger snake, Notechis scutatus scutatus
De Brabander et al. Nucleated assembly of mitotic microtubules in living PTK2 cells after release from nocodazole treatment
Eichhorn et al. Local anesthetic-induced inhibition of collagen secretion in cultured cells under conditions where microtubules are not depolymerized by these agents.
Tang et al. Adenylyl cyclase 6 deletion increases mortality during sustained β-adrenergic receptor stimulation
Sonoda et al. Electrical myotonia of rabbit skeletal muscles by HMG‐CoA reductase inhibitors
Wasterlain et al. Posthypoxic treatment with felbamate is neuroprotective in a rat model of hypoxia‐ischemia
JP2003535818A (en) Methods of identifying and using A2B adenosine receptor antagonists that mediate mammalian cell proliferation
Aliev et al. Changes in vessel ultrastructure during ischemia and reperfusion of rabbit hindlimb: implications for therapeutic intervention
Foster et al. Cellular pathology changes in rat skin following intradermal injection of nerve growth factor: neutrophil‐dependent and‐independent events
US20050064501A1 (en) Medicaments comprising inhibitors of the cell volume-regulated human kinase h-sgk
CN106943340A (en) A kind of lidocaine hydrochloride jelly
US6946457B2 (en) Methods of treating sickle cell disease
Altenburg et al. Adrenergic modulation of the blood neutrophilia induced by platelet activating factor in rats
Burnard et al. Altered sensitivity to arginine vasopressin (AVP) in area CA1 of the hippocampal slice following pretreatment of rats with AVP
Tiwari et al. Therapeutic Potential of HDAC Inhibitors in the Treatment of Cardiac Diseases: A Short Review
Barbagallo et al. Effectiveness of cascade filtration plasmapheresis in two patients affected by familial hypercholesterolemia
CN111671763B (en) Application of morroniside in preparing medicine for treating lysosome storage disease
CN1437477A (en) A Memory enhancing protein
Mahmood et al. Angiotensin-Converting Enzyme 2: A new component of renin-angiotensin system (RAS) and a receptor for SARS-coronavirus-2
CN114480625A (en) Use of MAPK signaling pathway inhibition for amelioration, diagnosis and treatment of chronic osteomyelitis
WO1990013027A1 (en) Process for detecting cells with foreign antigens or a modified surface structure

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C12 Rejection of a patent application after its publication
RJ01 Rejection of invention patent application after publication
REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1045949

Country of ref document: HK