EP1171131A1 - Arzneimittel enthaltend hemmstoffe der zellvolumenregulierten humanen kinase h-sgk - Google Patents

Arzneimittel enthaltend hemmstoffe der zellvolumenregulierten humanen kinase h-sgk

Info

Publication number
EP1171131A1
EP1171131A1 EP00922655A EP00922655A EP1171131A1 EP 1171131 A1 EP1171131 A1 EP 1171131A1 EP 00922655 A EP00922655 A EP 00922655A EP 00922655 A EP00922655 A EP 00922655A EP 1171131 A1 EP1171131 A1 EP 1171131A1
Authority
EP
European Patent Office
Prior art keywords
sgk
kinase
expression
human kinase
medicament
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.)
Withdrawn
Application number
EP00922655A
Other languages
German (de)
English (en)
French (fr)
Inventor
Florian Lang
Siegfried Waldegger
Carsten Wagner
Stefan Bröer
Karin Klingel
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 EP1171131A1 publication Critical patent/EP1171131A1/de
Withdrawn legal-status Critical Current

Links

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

Definitions

  • the present invention relates to medicaments containing inhibitors or activators of the cell volume regulated human kinase h-sgk.
  • Such drugs are suitable for the therapy of disease states in which an increased or decreased expression of the h-sgk is found.
  • the h-sgk and processes for their preparation have already been described in EP-0 861 896, the content of which is expressly intended to be part of the present description.
  • h-sgk human serum and glucocorticoid dependent kinase (serine / threonine kinase)
  • MDEG mammalian degenerin
  • BNC brain Na + - channel
  • TGFßi tumor growth factor ßi
  • NKCC Na + , K + , 2Cl ' transporters
  • Transdominant inhibitory kinase mutation-altered h-sgk: lysine at position 127 was replaced by arginine (K127R); the mutation lies in the catalytic region and prevents the catalytic function of the kinase.
  • Increased expression of h-sgk is increasingly found in diabetes mellitus, arteriosclerosis, Alzheimer's disease, liver cirrhosis, Crohn's disease, explosive pancreatitis, pulmonary fibrosis and chronic bronchitis.
  • the increased formation of h-sgk can be explained by stimulation of expression by TGFßi (Fig. 1). Fibrosive diseases are caused by increased formation and reduced breakdown of matrix proteins. Both are effects of TGFßi.
  • the increased Expression of the matrix proteins can be prevented by inhibiting the NKCC with furosemide (FIG. 2). So far it was unclear whether the increased expression of h-sgk is only the consequence or cause of the disease.
  • the stimulating effect of h-sgk on the ENaC can be prevented by kinase inhibitors, such as, for example, staurosporine (Sigma, D-82041 Deisenhofen) or chelerythrine (Sigma, loc. Cit.) (FIG. 4).
  • kinase inhibitors such as, for example, staurosporine (Sigma, D-82041 Deisenhofen) or chelerythrine (Sigma, loc. Cit.) (FIG. 4).
  • the effect of h-sgk on the ENaC can be suppressed, for example, by transdominant inhibitory kinase (FIG. 5).
  • Inhibitors of h-sgk such as staurosporine, chelerythrine or other kinase inhibitors, could therefore be used in the therapy of the abovementioned diseases.
  • all known kinase inhibitors can be used.
  • kinase inhibitors are also commercially available in many cases, for example from Calbiochem-Novabiochem GmbH, Lisztweg 1, D-65812 Bad Soden (see “1998 General Catalog”). Additional kinase inhibitors are available from other commercial and non-commercial sources known to those skilled in the art.
  • the h-sgk is increasingly expressed in epileptic seizures.
  • the functional data we found show that the effects are suitable for reducing the excitability of neurons, since the activation of the NKCC leads to a decrease in the extracellular K + concentration, which results in hyperpolarization and thus inhibition of the activity of neurons .
  • inhibition of MDEG should inhibit neuronal excitability. Accordingly, activators of the kinase that cross the blood-brain barrier could be used successfully in epileptic seizures. Conversely, inhibition of the kinase with pharmaceuticals that cross the blood-brain barrier could increase attention and the ability to learn.
  • Activators of kinases have also long been known to the person skilled in the art, of which the protein kinase C activators are of particular interest (see, for example, Calbiochem-Novabiochem 1998 General Catalog, loc. Cit.). Additional kinase activators are available from other commercial and non-commercial sources known to those skilled in the art. Since the Na + , K + , 2Cr cotransport and the Na + channel are crucial for renal Na + absorption and an increased renal Na + absorption is associated with hypertension, it must be assumed that increased expression of the kinase increases Hypertension and decreased expression of the kinase lead to hypotension.
  • the present invention thus also relates to the use of inhibitors of h-sgk for the production of medicaments for the treatment of diabetes mellitus, arteriosclerosis, M. Alzheimer's, liver cirrhosis, M. Crohn, fibrosing pancreatitis, pulmonary fibrosis, chronic bronchitis, radiation fibrosis, scleroderma, cystic fibrosis and other fibrosing diseases and for the treatment of arterial hypertension.
  • medicinal products containing inhibitors or activators of h-sgk can be used to regulate neuronal excitability.
  • the use of the inhibitors staurosporine or chelerythrine and their analogs is particularly advantageous.
  • the h-sgk is expressed only sparingly in the normal kidney. Individual cells in the glomerulum, late proximal and distal tubules show clear h-sgk expression. In contrast, there are clusters of cells with massive h-sgk expression in the diabetic kidney.
  • Massively h-sgk-expressing cells are increasingly found in the vessel walls of arteriosclerotic vessels.
  • Alzheimer There are only a few cells in the normal brain that express h-sgk. These cells are probably oligodentroglia cells. In brains with Alzheimer's disease, the number of h-sgk-expressing cells has increased significantly.
  • the h-sgk In normal intestinal tissue, the h-sgk is only expressed in the enterocytes. In Crohn's disease, however, the kinase is also found in the connective tissue.
  • Fibrosive pancreatitis In the normal pancreas, the h-sgk is found in acinar cells and also in gang cells. There are isolated h-sgk-expressing mononuclear cells around the pancreatic ducts. The expression of kinase is significantly increased in fibrosing pancreatitis.
  • TGFß TGFß ! stimulated (Fig. 1). Since TGFßj is formed in fibrosis-inflamed tissue, this finding explains the increased expression of h-sgk in inflamed tissue. TGFßi stimulates the expression of the matrix protein Biglycan, an effect that is prevented by the NKCC inhibitor furosemide:
  • TGFßi stimulates the expression of biglycan.
  • the NKCC inhibitor furosemide the effect of TGFßi on biglycan expression is completely prevented.
  • the fibrosing effect of TGFßi therefore requires activation of the NKCC (Fig. 2).
  • the stimulation of the epithelial ENaC by the h-sgk can be reversed by coexpression of the transdominant-inhibitory kinase h-sgk: As FIG. 5 shows, the stimulating effect of the h-sgk coexpression on the ENaC-mediated Na + current can be reversed Co-expression of a transdominant inhibitory kinase can be prevented.
  • This transdominant-inhibitory kinase (compare with "definitions") is so modified on the catalytic unit that it can no longer function. However, since it attaches to the substrate, it displaces the active kinase and thus suppresses its effect.
  • the transdominant-inhibitory kinase not only prevents the increase in ENaC activity by exogenous h-sgk, but also apparently suppresses stimulation by the endogenous h-sgk.
  • MDEG is completely switched off by coexpression with h-sgk: As FIG. 6 shows, the expression of MDEG in oocytes induces a strong Na + current, which is activated by lowering the extracellular pH. The channel is completely blocked by coexpression with h-sgk. It must be concluded from this that the h-sgk inhibits neuronal excitability. Examples:
  • Tissues from normal pancreas, liver, vessels, brain, lungs, kidney and intestines, as well as tissues with diabetic nephropathy, arteriosclerosis, Alzheimer's disease, liver cirrhosis, Crohn's disease, fibrosing pancreatitis and pulmonary fibrosis were found in 4% paraformaldehyde / 0.1 M sodium phosphate Buffer (pH 7.2) embedded in Praffm for 4 hours.
  • Tissue sections were dewaxed and hybridized as previously described (Kandolf, R., D. Ameis, P. Kirschner, A. Canu, PH Hofschneider, Proc. Natl. Acad. Sci.
  • the hybridization mixture contained either 35 S-labeled sense RNA coding for h-sgk or 35 S-labeled antisense RNA (500 ng / ml in each case) complementary to the latter in 10 mM Tris-HCl, pH 7.4; 50% (vol / vol) deionized formamide; 600 mM NaCl; 1mM EDTA; 0.02% polyvinyl pyrrolidone; 0.02% Ficoll; 0.05% calf serum albumin; 10% dextran sulfate; 10 mM dithiothreitol; 200 ⁇ g / ml denatured sonicated salmon sperm DNA and 100 ⁇ g / ml rabbit liver tRNA.
  • Hybridization with RNA samples was carried out at 42 ° C for 18 hours. The slides were washed as described (Hohenadl et al., 1991; Klingel et al., 1992), and then incubated for 1 hour at 55 ° C. in 2x standard sodium citrate. Non-hybridized single-stranded RNA samples were digested by RNase A (20 ⁇ g / ml) in 10 mM Tris-HCl, pH 8.0 / 0.5 M NaCl for 30 min at 37 ° C. Tissue samples were then autoradiographed for three weeks (Klingel et al., 1992) and stained with hematoxylin / eosin.
  • Example 2 Transcriptional regulation of Biglykan and the h-sgk.
  • DIG-Easy-Hyb The digoxigenin (DIG) labeled samples were generated by PCR as previously described in detail (Waldegger et al. (1997) PNAS 94: 4440-4445). For autoradiography, the filters were averaged 5 min. exposed to an X-ray film (Kodak).
  • Example 3 Two-electrode voltage clamp and tracer flow experiments.
  • the dissection of Xenopus laevis, the extraction and treatment of the oocytes have been described in detail earlier (Busch et al. 1992).
  • the oocytes were each cultured with 1 ng of
  • NKCC NKCC, ENaC or MDEG injected with or without simultaneous injection of the h-sgk.
  • Two-electrode voltage and current clamp experiments could be carried out 2-8 days after the injection. Furosemide inhibitable Na + influx through the NKCC was by
  • Na + uptake in the oocytes was determined, which was determined using a scintillation counter.
  • Na + currents (ENaC) were filtered at 10 Hz and recorded with a recorder.
  • Bath solution contained: 96 mM NaCl, 2 mM KC1, 1.8 mM CaCl 2 , 1 mM MgCl 2 , and 5 mM HEPES at pH 7.5 and the holding potential was -50 mV.
  • the pH was adjusted by titration with HC1 or NaOH.
  • the flow rate of the bath liquid was set to 20 ml / min, resulting in a complete change of solution in the measuring chamber within
  • h-sgk is stimulated by TGFßi.
  • TGFßi The effect of TGFß is shown after 0.5 to 6h (top).
  • Phorbol ester PDD (4-alpha-phorbol-12,13-didecanoate; stimulates protein kinase C) and Ca ⁇ ionophore ionomycin (Sigma, loc. Cit .; increases intracellular Ca ⁇ concentration) also stimulate h-sgk expression ( below).
  • NKCC osmotic cell swelling
  • Fig. 4 Stimulation of the ENaC by h-sgk:
  • the current through the ENaC (I) increases massively through co-expression with h-sgk.
  • Treatment of the oocytes with the kinase inhibitors staurosporin (S) or chelerythrin (C) prevents the activation of the Na + channel by h-sgk.
  • the stimulation of the ENaC by h-sgk can be reversed by coexpression of the transdominant-inhibitory kinase: Oocytes that express ENaC and h-sgk simultaneously have much larger currents (I) than oocytes that only express ENaC. Co-expression of the transdominant-inhibitory kinase prevents stimulation of the ENaC by the h-sgk.
  • the current through the MDEG (I) increases with the duration of the incubation [day (T) 1 - 4].

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Diabetes (AREA)
  • Neurology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Immunology (AREA)
  • Cardiology (AREA)
  • Pulmonology (AREA)
  • Emergency Medicine (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Obesity (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Dermatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Urology & Nephrology (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)
EP00922655A 1999-04-20 2000-04-19 Arzneimittel enthaltend hemmstoffe der zellvolumenregulierten humanen kinase h-sgk Withdrawn EP1171131A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19917990A DE19917990A1 (de) 1999-04-20 1999-04-20 Arzneimittel enthaltend Hemmstoffe der zellvolumenregulierten humanen Kinase h-sgk
DE19917990 1999-04-20
PCT/EP2000/003578 WO2000062781A1 (de) 1999-04-20 2000-04-19 Arzneimittel enthaltend hemmstoffe der zellvolumenregulierten humanen kinase h-sgk

Publications (1)

Publication Number Publication Date
EP1171131A1 true EP1171131A1 (de) 2002-01-16

Family

ID=7905297

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00922655A Withdrawn EP1171131A1 (de) 1999-04-20 2000-04-19 Arzneimittel enthaltend hemmstoffe der zellvolumenregulierten humanen kinase h-sgk

Country Status (18)

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

Families Citing this family (33)

* 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
DE10225844A1 (de) * 2002-06-04 2003-12-18 Lang Florian sgk und nedd als diagnostische und therapeutische targets
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
AU2003215623B2 (en) * 2003-03-03 2009-10-22 Florian Lang 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 (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
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

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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0062781A1 *

Also Published As

Publication number Publication date
PL352547A1 (en) 2003-08-25
KR100718900B1 (ko) 2007-05-17
PL198427B1 (pl) 2008-06-30
NO20015054D0 (no) 2001-10-17
CN1351496A (zh) 2002-05-29
NO20015054L (no) 2001-12-14
MXPA01010588A (es) 2004-09-06
DE19917990A1 (de) 2000-11-02
CA2369078A1 (en) 2000-10-26
JP2002542196A (ja) 2002-12-10
AU4297200A (en) 2000-11-02
AU779941B2 (en) 2005-02-17
HUP0200819A2 (hu) 2002-07-29
HUP0200819A3 (en) 2009-08-28
RU2288718C9 (ru) 2008-04-27
SK14972001A3 (sk) 2002-06-04
CZ20013778A3 (cs) 2002-06-12
BR0009914A (pt) 2002-01-08
RU2288718C2 (ru) 2006-12-10
ZA200108610B (en) 2002-01-02
KR20020012172A (ko) 2002-02-15
UA79066C2 (en) 2007-05-25
WO2000062781A1 (de) 2000-10-26

Similar Documents

Publication Publication Date Title
EP1171131A1 (de) Arzneimittel enthaltend hemmstoffe der zellvolumenregulierten humanen kinase h-sgk
DE69535462T2 (de) Zusammensetzung und Verfahren zur Inhibition der Filamentbildung des Amyloid-Betaproteins und seiner Neutotoxizität
DE69636997T2 (de) HEILUNG UND VORBEUGUNG VON DURCH NF-kappaB VERURSACHTEN ERKRANKUNGEN
DE60313125T2 (de) Verwendung von erythropoietin zur behandlung oder vorbeugung von herzversagen
DE69637104T2 (de) Heilmittel für arthrosis deformans und entzündliche gelenkerkrankungen
EP1617858B1 (de) Caspase 3, 8, 9 oder 10 Inhibitoren in Kombination mit MEK Inhibitoren zur Behandlung von Influenza
EP2242738B1 (de) Sgk1-inhibitoren zur prophylaxe und/oder therapie von viralen erkrankungen und/oder karzinomen
DE69624253T2 (de) Ati-rezeptorantagonisten zur verhinderung und behandlung des postischemischen nervenversagens und zum schutze ischemischer nieren
EP1056467B1 (de) Verfahren zur behandlung von erkrankungen oder störungen des innenohrs
EP0655242A1 (de) Verwendung von Cumarinderivaten bei NO-induzierten Krankheiten
EP1313476B1 (de) SGK3 ALS DIAGNOSTISCHEs UND THERAPEUTISCHEs TARGET
US20050064501A1 (en) Medicaments comprising inhibitors of the cell volume-regulated human kinase h-sgk
DE69607417T2 (de) Verwendung von Batroxobin enthaltende Arzneimittel zur Behandlung und Prophylaxe von ischämischen Reperfusionsschäden
DE19744676A1 (de) Kombinationspräparate für die Therapie von Tumoren
Erickson et al. Altered functional expression of Purkinje cell calcium channels precedes motor dysfunction in tottering mice
DE2349538A1 (de) Arzneimittel zur behandlung von lebererkrankungen
DE60110628T2 (de) Antiphlogistische mittel
DE602004011843T2 (de) Die myocardfunktion wiederherstellende peptidsubstanz
Maiese Neuronal and vascular plasticity: Elucidating basic cellular mechanisms for future therapeutic discovery
Bass et al. Action of hydrocortisone sodium succinate on HeLa cells
DE10234901A1 (de) Verwendung von am Mrp4 bindenden Substanzen zur Diagnose und Behandlung von Krebserkrankungen
EP1080192A2 (de) Antisense-oligonukleotide zur behandlung von proliferierenden zellen
Petkov et al. Synthetic Plant Growth Regulators as Possible Psychotropic Drugs: I. Behavioural Studies on Rats
HK1045949A (en) Medicaments containing inhibitors of cell-volume regulated human kinase h-sgk
WO2004022102A2 (de) Pharmazeutische formulierung mit nichtsteroidalen antiphlogistika und nukleinsäuren zur einschleusung von nukleinsäuren in eukaryotischen zellen

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20011031

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL;LT PAYMENT 20011031;LV PAYMENT 20011031;MK;RO PAYMENT 20011031;SI PAYMENT 20011031

17Q First examination report despatched

Effective date: 20040430

RTI1 Title (correction)

Free format text: MEDICAMENT CONTAINING AN INHIBITOR OF HUMAN KINASE H-SGK (CHELERYTHRIN) FOR FIBROTIC DISEASES

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20081016