EP1811997A2 - Niedermolekulare inhibitoren von guaninnucleotid-austauschfaktoren der cytohesin-familie - Google Patents
Niedermolekulare inhibitoren von guaninnucleotid-austauschfaktoren der cytohesin-familieInfo
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- EP1811997A2 EP1811997A2 EP05810998A EP05810998A EP1811997A2 EP 1811997 A2 EP1811997 A2 EP 1811997A2 EP 05810998 A EP05810998 A EP 05810998A EP 05810998 A EP05810998 A EP 05810998A EP 1811997 A2 EP1811997 A2 EP 1811997A2
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- European Patent Office
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
- G01N2500/02—Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
Definitions
- the present invention relates to pharmaceuticals.
- the medicine can be used for the treatment of autoimmune diseases, tumor diseases and / or for immunosuppression.
- These regulatory proteins or exchange factors fulfill the SAM: AL despite a partially very homologous structure Different tasks in the cell context highly specific, with some proteins are selectively involved in the development of certain diseases.
- Guanine nucleotide exchange factors also referred to as GEFs, activate small G proteins by stimulating GDP / GTP exchange. Guanine nucleotide exchange factors are regulators of activation signals.
- Guanine nucleotide replacement factors for small GTPases of the family of ADP ribosylation factors (ARFs) include the family of large guanine nucleotide exchange factors, such as Geal, Gea2, BlGl, B1G2, and the small family
- cytohesins such as cytohesin-1, cytohesin-2, cytohesin-3 and cytohesin-4 (Julie G Donaldson and Catherine L Jackson, Regulators and effectors of the ARF GTPases, Current Opinion in Cell Biology 2000, 12: 475) 182).
- a common feature of the guanine nucleotide exchange factors for small ADP ribosylation factor GTPases is their central sec7 domain, corresponding to amino acids 62-244 in cytohesin-1 (Ref: Betz et al, Proc Natl Acad Sci USA 1998 JuI 7; 95 (14): 7909-14), cytohesin-2 (Chardin, P. et al., Nature 384, 481-4 (1996) or Gea2 (Peyroche, A. et al., Mol Cell 3, 275- 85 (1999)).
- the sec7 domain is broadly similar within the guanine nucleotide exchange factors and responsible for the catalysis of guanine nucleotide exchange.
- Cytohesins have a molecular weight of about 50 kDa and are involved in the regulation of cell proliferation and cell adhesion / migration in cancer cells and immune cells.
- Brefeldin A as well as RNA aptamers and peptides, which are either highly toxic or not sufficiently cell-tolerated and therefore not medically applicable, are known as inhibitors of GEFs.
- replacement factors of the cytohesin family have so far not suitable as molecular targets for medical applications.
- Other compounds that inhibit these proteins are not previously known in the art.
- the object of the present invention was to provide compounds useful as inhibitors of the cytohesin family of GEFs, pharmaceutical compositions comprising these compounds and their use in the treatment of diseases by means of these inhibitors.
- a medicament comprising compounds selected from the group comprising the general formulas (1), (2), (3), (4) and / or their enantiomers, diastereomers and pharmaceutically acceptable salts thereof:
- R is selected from the group comprising hydrogen, OH, COOH, COO (C 1 -C 10 -alkyl), CONH 2 , CONH (C 1 -C 18 -alkyl), CON (C 1 -C 4 -alkyl) 2 , halogen, preferably selected from among Group comprising Cl, Br, F, amine, Cl-ClO- - A -
- R 4 is selected from the group comprising hydrogen, OH, COOH, COO (Cl-
- ClO-alkyl CONH 2 , CONH (Cl-ClO-alkyl), CON (Cl-ClO-alkyl) 2 , halogen, preferably selected from the group comprising Cl, Br, F, amine and / or Cl-ClO-alkoxy.
- a particular advantage of the compounds selected from the group comprising the general formulas (1), (2), (3), (4) is that they can inhibit the proteins at concentrations which are non-toxic.
- the compounds provided in particular selected from the group comprising the general formulas (1), (2), (3), (4) can be used in medicaments and / or used therapeutically.
- the compounds are preferably low molecular weight compounds.
- low molecular weight compounds are compounds which preferably have a molecular weight in the range from 50 daltons to 800 daltons, preferably in the range from 100 daltons to 500 daltons, more preferably in the range from 250 daltons to 475 daltons.
- the compounds selected from the group comprising the general formulas (1), (2), (3), (4) have a molecular weight of less than 500 daltons.
- the compounds comprising the compounds selected from the group comprising the general formulas (1), (2), (3), (4) is realized in that the compounds are cell-like.
- the compounds are advantageously very good cell-like, whereby a very high availability of the compounds at their site of action, especially in cells can be achieved.
- the term "cell-like" means that the compounds can pass through the cell membrane and enter cells. In particularly advantageous embodiments, the compounds reach completely or almost completely into the cells and / or are completely or almost completely available in the cell.
- the medicaments comprising cell-permeable compounds selected from the group comprising the general formulas (1), (2), (3), (4) can thus be administered by conventional methods, for example orally, dermally and / or intravenously, without the compounds having to be introduced into the cell by means of transfection.
- the drug comprises compounds selected from the group comprising the general formulas (1), (2), (3), (4), wherein the structural elements R 1 , R 2 and / or R 3 are preferably selected from the sulfur-containing structural elements (Al), (Bl), (Cl) and / or (Dl).
- the drug may comprise compounds which have a plurality of identical and / or different structural elements (Al), (Bl), (Cl) and / or (Dl).
- the compounds preferably have at least one, preferably two, more preferably three identical and / or different structural elements (A1), (B1), (C1) and / or (D1).
- drugs comprise compounds selected from the group comprising the general formulas (5), (6), (7), (8) as indicated below and / or their enantiomers, diastereomers and their pharmaceutically acceptable salts:
- Ri is selected from the group comprising R 2 , R 3 and / or a structural element (A2), (B2), (C2), (D2) as indicated below:
- R 2 is selected from the group comprising R 1 , R 3 and / or a structural element (E2), (F 2 ), (G 2 ), (H 2 ), (12), (J 2 ), (K 2 ) as indicated below:
- R 3 is selected from the group comprising R 1 , R 2 , and / or selected from the group
- the drug comprises compounds selected from the group comprising the general formulas (5), (6), (7), (8), wherein the structural elements R 1 , R 2 and / or R 3 are preferably selected from the sulfur-containing
- the drug may comprise compounds which have a plurality of identical and / or different structural elements (A2), (B2), (C2) and / or (D2).
- the compounds preferably have at least one, preferably two, more preferably three identical and / or different structural elements (A2), (B2), (C2) and / or (D2).
- Preferred among the C 1 -C 10 alkoxy groups are methoxy and / or ethoxy groups.
- Particularly suitable drugs according to the invention include compounds selected from the group comprising the general formulas (5), (6), (7), (8) as indicated below and / or their enantiomers, diastereomers and pharmaceutically acceptable salts thereof:
- R 1 is selected from the group comprising R 2 , R 3 and / or a structural element
- R 2 is selected from the group comprising R 1 , R 3 and / or a structural element (E3), (F3), (G3), (H3), (13), (J3), (K3), as indicated below:
- R 3 is selected from the group comprising R 1 , R 2 , and / or selected from the group comprising hydrogen, OH, COOH, COO (Cl-ClO-alkyl), CONH 2 , CONH (Cl-ClO-alkyl), CON (Cl-ClO-alkyl) 2 , halogen, preferably selected from the group comprising Cl, Br, F, and / or Cl-C10-alkoxy.
- the drug comprises compounds selected from the group comprising the general formulas (5), (6), (7), (8), wherein the Structural elements R 1 , R 2 and / or R 3 are preferably selected from the sulfur-containing structural elements (A3), (B3), (C3) and / or (D3).
- the drug may comprise compounds which have a plurality of identical and / or different structural elements (A3), (B3), (C3) and / or (D3).
- the compounds preferably have at least one, preferably two, more preferably three identical and / or different structural elements (A3), (B3), (C3) and / or (D3).
- the drug comprises compounds selected from the group comprising compounds (9), (10), (11), (12), (13), (14) as indicated below and / or their enantiomers, diastereomers and their pharmaceutically acceptable salts:
- a preferred enantiomer of the compounds selected from the group comprising compounds (9), (10), (11), (12), (13) and / or (14) is the compound (19) as indicated below:
- the drug comprises compounds selected from the group comprising the general formulas (20) and / or (21) and / or their enantiomers, diastereomers and pharmaceutically acceptable salts thereof:
- the drug may comprise the compounds (20) and / or (21) as monomers and / or dimers, trimers and / or oligomers.
- the compounds selected from the group comprising the general formulas (20) and / or (21) preferably have
- Dissociation constants in the range of 0.1 uM to 30 uM can have IC 50 values of from 0.1 ⁇ M to 30 ⁇ M, particularly preferably in the range from 0.5 ⁇ M to 20 ⁇ M, very particularly preferably Range from 1 ⁇ M to 15 ⁇ M.
- the medicament of the invention may comprise the compounds selected from the group comprising the general formulas (1), (2), (3), (4), (5), (6), (7) and / or (8) preferably selected from of the group comprising compounds (9), (10), (11), (12), (13) and / or (14), (20) and / or (21) as monomers.
- the medicament comprises dimers, trimers and / or oligomers which contain at least one or more of the monomers selected from the group comprising the general formulas (1), (2), (3), (4), (5) , (6), (7) and / or (8), preferably selected from the group comprising compounds (9), (10), (11), (12) (13) and / or (14), (20) and / or (21).
- the connecting groups or spacer can connect the individual units and / or monomers rigidly or flexibly.
- individual moieties and / or monomers can be rigidly attached through alkyne groups, while a moiety via one or more ethylene glycol moiety (s) can provide a flexible compound.
- a further advantage of the medicament according to the invention can be achieved by the fact that even small therapeutic dosages of the medicament can be used.
- a high dosage which can often lead to toxic side effects, can be avoided by the very well cell-permeable and widely available compounds.
- the compounds selected from the group comprising the general formulas (1), (2), (3), (4), (5), (6), (7) and / or (8) preferably selected from the group comprising compounds (9), (10), (11), (12), (13) and / or (14), (20) and / or (21) dissociation constants in the range from 0.1 ⁇ M to 30 ⁇ M, especially preferred in Range of 0.5 uM to 10 uM, most preferably in the range of 1 uM to 7 uM on.
- the dissociation constants are determined by microcalorimetry.
- the dissociation constant preferably refers to the binding of the compounds to sec-7 domains of the cytohesins.
- the compounds selected from the group comprising the general formulas (1), (2), (3), (4), (5), (6), (7) and / or (8) are preferably selected of the group comprising compounds (9), (10), (11), (12), (13) and / or (14) IC50 values in the range of 0.1 ⁇ M to 30 ⁇ M, particularly preferably in the range of 0.5 ⁇ M to 20 ⁇ M, most preferably in the range of 1 ⁇ M to 15 ⁇ M on.
- the IC 50 value of the compounds for inhibiting the exchange activity of the sec 7 domains of various guanine nucleotide exchange factors corresponds to the concentration necessary to reduce the activity of the protein by half.
- a particular advantage of the compounds provided and the pharmaceuticals containing these compounds may be that the compounds preferably leave the Golgi apparatus-dependent cellular functions intact. This means in particular an advantage over Brefeldin A, which destroys the Golgi apparatus of the cells.
- the drug comprises, based on a daily dose, 10 nM to 100 ⁇ M, preferably 100 nM to 10 ⁇ M, preferably 1 ⁇ M to 10 ⁇ M, more preferably 1 ⁇ M to 3 ⁇ M compound (s) selected from the group comprising the general Formulas (1), (2), (3), (4), (5), (6), (7) and / or (8) preferably selected from the group comprising compounds (9), (10), ( 11), (12), (13) and / or (14) and / or their enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
- 10 nM to 100 ⁇ M preferably 100 nM to 10 ⁇ M, preferably 1 ⁇ M to 10 ⁇ M, more preferably 1 ⁇ M to 3 ⁇ M compound (s) selected from the group comprising the general Formulas (1), (2), (3), (4), (5), (6), (7) and / or (8) preferably selected from the group comprising compounds (9), (10), ( 11), (12), (13) and / or (1
- the drug comprises, based on a daily dose, 10 nM to 100 ⁇ M, preferably 100 nM to 10 ⁇ M, preferably 1 ⁇ M to 10 ⁇ M, more preferably 1 ⁇ M to 3 ⁇ M, even more preferably 500 nM to 3 ⁇ M, more preferably 500 nM to 1 ⁇ M compound (s) selected from the group comprising the general formulas (20) and / or (21) and / or their enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
- 10 nM to 100 ⁇ M preferably 100 nM to 10 ⁇ M, preferably 1 ⁇ M to 10 ⁇ M, more preferably 1 ⁇ M to 3 ⁇ M, even more preferably 500 nM to 3 ⁇ M, more preferably 500 nM to 1 ⁇ M compound (s) selected from the group comprising the general formulas (20) and / or (21) and / or their enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
- the medicament comprises, based on a daily dose, 500 nM to 3 ⁇ M, preferably 500 nM to 1 ⁇ M compound (s) selected from the group comprising the general formulas (1), (2), (3), ( 4), (5), (6), (7) and / or (8) preferably selected from the group comprising compounds (9), (10), (11), (12), (13) and / or ( 14), (20) and / or (21).
- compound (s) selected from the group comprising the general formulas (1), (2), (3), ( 4), (5), (6), (7) and / or (8) preferably selected from the group comprising compounds (9), (10), (11), (12), (13) and / or ( 14), (20) and / or (21).
- a daily dose means the amount of the drug administered per day.
- the compounds selected from the group comprising the general formulas (1), (2), (3), (4), (5), (6), (7) and / or (8) preferably selected from the group comprising compounds (9), (10), (11), (12), (13), (14) and / or (19), (20) and / or (21) may alter the activity of guanine nucleotide exchange factors conferring sec7 Domain, where the modulation is a blockage or inhibition.
- compounds selected from the group comprising the general formulas (1), (2), (3), (4), (5), (6), (7) and / or (8) are preferably selected from the group comprising compounds (9), (10), (11), (12), (13), (14) and / or (19), (20) and / or (21) and / or their enantiomers, diastereomers and their pharmaceutically acceptable salts are useful as inhibitors for proteins having at least one sec7 domain.
- These compounds are useful as inhibitors of sec7 domain-containing proteins, which proteins are preferably selected from the group comprising guanine nucleotide exchange factors, preferably selected from the group comprising guanine nucleotide exchange factors for human ADP ribosylation factors, such as Geal, Gea2, BlGl, B1G2 and / or cytohesins such as cytohesin-1, cytohesin-2, cytohesin-3 and / or cytohesin-4.
- proteins are preferably selected from the group comprising guanine nucleotide exchange factors, preferably selected from the group comprising guanine nucleotide exchange factors for human ADP ribosylation factors, such as Geal, Gea2, BlGl, B1G2 and / or cytohesins such as cytohesin-1, cytohesin-2, cytohesin-3 and / or cytohesin-4.
- the compounds selected from the group comprising the compounds (9), (10), (11), (12), (13), (14) and / or (19), (20) and / or (21) are particularly useful for the inhibition of cytohesins.
- an advantage of the compounds in preferred embodiments is that these compounds can specifically bind to cytohesins.
- the compounds can bind to cytohesins while the compounds bind to higher molecular weight guanine nucleotide exchange factors such as Geal, Gea2, BlGl, B1G2 at these concentrations do not or only to a lesser extent bind.
- the binding constant for the binding of the compounds, in particular compound (9), to the sec-7 domain of human cytohesins can be in the range of 100 nM to 1500 nM, preferably in the range of 200 nM to 900 nM, preferably in the range of 200 nM to 500 nM, lie.
- the compounds may have specificity for certain cytohesins, for example compound (12) may preferentially bind to cytohesin-1 over cytohesin-2.
- compound (12) may preferentially bind to cytohesin-1 over cytohesin-2.
- compounds of the invention which preferentially bind to cytohesin-1 to cytohesin-3 and thus specifically inhibit it, may allow the possibility of using the compounds to treat type II diabetes.
- the inhibition constants (Kj values) of the compounds provided to cytohesins in insulin signaling can be in the range from 7 ⁇ M to 20 ⁇ M.
- the specificity of the compounds may be affected by the concentration of the compounds, for example, specificity to certain cytohesins may occur at higher or lower concentrations of the compounds. This allows the use of the compounds in certain concentration ranges, in so-called therapeutic windows, for the inhibition of certain cytohesins.
- blocking is understood to mean binding of the compounds (15), (16), (17), (18) to the sec7 domain of the proteins, which preferably has an inhibition of the sec7 domain Proteins, especially the cytohesins, leads.
- the structural elements which comprise the compounds may be selected from the group comprising R, R 1 , R 2 R 3 , and / or R 4 , structural elements (Al), (Bl), (Cl), (Dl), ( El), (Fl), (Gl), (HI), (II), (JI), (A2), (B2), (C2), (D2), (E2), (F2), (G2) , (H2), (12), (J2), (K2), (A3), (B3), (C3), (D3), (E3), (F3), (G3), (H3), ( 13), (J3), (K3), hydrogen, OH, COOH, COO (Cl-ClO-alkyl), CONH 2 , CONH (Cl-ClO-alkyl), CON (Cl-ClO-alkyl) 2 , halogen, preferably selected from the group comprising Cl, Br, F, amine, C 1 -C 10 -alkoxy, alky
- Alkyl linear or branched C 1 -C 2 O-alkyl, preferably ethyl, propyl, iso-propyl, tert-butyl, butyl, pentane.
- Alkenyl C 2 -C 20 -alkenyl.
- Alkynyl C 2 -C 20 alkynyl.
- Cycloalkyl C 3 -C 10 -cycloalkyl.
- Alkoxy C 1 -Q-AIkOXy.
- Alkylene methylene; 1,1-ethylene; 1,2-ethylene; 1,1-propylidene; 1,2-propylene; 1,3-propylene; 2,2-propylidene; Butan-2-ol-l, 4-diyl; Propan-2-ol-l, 3-diyl; 1,4-butylene; C) clohexan-l, l-diyl; Cyclohexane-l, 2-diyl; Cyclohexane-l, 3-diyl; Cyclohexane-l, 4-diyl; C) clopentan-l, l-diyl; Cyclopentane-l, 2-diyl; and / or cyclopentane-1,3-diyl.
- Arylene 1,2-phenylene; 1,3-phenylene; 1,4-phenylene; 1,2-naphtalenylene; 1,3-naphtalenylene; 1,4-naphtalenylene; 2,3-naphtalenylene; l-hydroxy-2,3-phenylene; l-hydroxy-2,4-phenylene; 1-hydroxy-2,5-phenylene; and / or 1-hydroxy-2,6-phenylene.
- Heteroaryl pyridinyl; pyrimidinyl; pyrazinyl; triazolyl; pyridazinyl; 1,3,5-triazinyl;
- Quinolinyl isoquinolinyl; quinoxalinyl; imidazolyl; pyrazolyl; benzimidazolyl; thiazolyl; oxazolidinyl; pyrrolyl; carbazolyl; indolyl; and / or isoindolyl.
- Heteroarylene pyridinediyl; Quinolindiyl; Pyrazodiyl; pyrazoldiyl; Triazolediyl; pyrazinediyl; and / or imidazolediyl; in particular pyridine-2,3-diyl; Pyridine-2,4-diyl; Pyridine-2,5-diyl; Pyridine-2,6-diyl; Pyridine-3,4-diyl; Pyridine-3,5-diyl; Quinoline-2,3-diyl; Quinoline-2,4-diyl; Quinoline-2,8-diyl; Isoquinoline-l, 3-diyl; Isoquinoline-l, 4-diyl; Pyrazol-l, 3-diyl; Pyrazole-3,5-diyl; Triazole-3,5-diyl; Triazole-l, 3-diyl;
- Cl-C6 heterocycloalkyl piperidinyl; piperidines; 1,4-piperazines, tetrahydrothiophenes; tetrahydrofuran; 1,4,7-triazacyclononane; 1,4,8,11-tetraazacyclotetradecane; 1,4,7,10,13-pentaaza-cyclopentadecane; 1, 4-diaza- 7-thiacyclononane; 1, 4-diaza-7-oxa-cyclononane; 1,4,7,10-tetraazacyclododecane; 1,4-dioxane; 1,4,7-trithiacyclononane; pyrrolidine; and / or tetrahydropyran.
- Heterocycloalkylene piperidin-1, 2-ylene; Piperidin-2,6-ylene; Piperidin-4,4-ylidene; 1,4-piperazine-1,4-ylene; l, 4-piperazine-2,3-ylene; l, 4-piperazine-2,5-ylene; l, 4-piperazine-2,6-ylene; l, 4-piperazine-l, 2-ylene; l, 4-piperazine-l, 3-ylene; l, 4-piperazine-l, 4-ylene; Tetrahydrothiophene-2,5-ylene; Tetrahydrothiophene 3,4-ylene; Tetrahydrothiophene-2,3-ylene; Tetrahydrofuran-2,5-ylene; Tetrahydrofuran-3,4-ylene; Tetrahydrofuran-2,3-ylene; Pyrrolidin-2,5-ylene; Pyrrolidin-3,4-ylene; Pyrrolidin-2,3-ylene
- Heterocycloalkyl pyrrolinyl; pyrrolidinyl; morpholinyl; piperidinyl; piperazinyl; hexamethyleneimines; 1,4-piperazinyl; tetrahydrothiophenyl; tetrahydrofuranyl; 1,4,7-triazacyclononanyl; 1,4,8,11-tetraazacyclotetradecanyl; 1,4,7,10,13-pentaaza-cyclopentadecanyl; l, 4-diaza-7-thiacyclononanyl; l, 4-diaza-7-oxa-cyclononanyl; 1, 4,7,10-tetraazacyclododecanyl; 1, 4-dioxanyl; 1, 4,7-trioxanyl;
- Amines -N (R) 2 wherein each R is independently selected from the group comprising: H; Cl-C6 alkyl; Cl-C6-alkyl-C6H5; and / or phenyl, where both R can form a - NC3 to -NC5 heterocyclic ring closure.
- Halogen F; Cl; Br and / or I, more preferably F.
- Carboxylate derivatives -C (O) OR, wherein R is selected from the group comprising: H; Cl-C20-alkyl; phenyl; Cl-C6-alkyl-C6H5; Li; N / A; K; Cs; mg; and / or Ca.
- Phosphonate -P (O) (OR) 2, wherein each R is independently selected from the group comprising: H; Cl-C6 alkyl; phenyl; Cl-C6-alkyl-C6H5; Li; N / A; K; Cs; mg; and / or Ca.
- Phosphate -OP (O) (OR) 2, wherein each R is independently selected from the group comprising: H; Cl-C6 alkyl; phenyl; Cl-C6-alkyl-C6H5; Li; N / A; K; Cs; mg; and / or Ca.
- Phosphine -P (R) 2, wherein each R is independently selected from the group comprising: H; Cl-C6 alkyl; phenyl; Cl-COE-alkyl-CöHS.
- compounds selected from the group comprising the general formulas (1), (2), (3), (4), (5), (6), (7) and / or (8) are preferably selected from the group comprising compounds (9), (10), (11), (12), (13) and / or (14), (20) and / or (21) and / or their enantiomers, diastereomers and their pharmaceutically acceptable salts
- the object of the invention is further achieved by compounds which bind to proteins having at least one sec7 domain, the compounds being selected from the group comprising the general formulas (1), (2), (3), (4), ( 5), (6), (7) and / or (8) preferably selected from the group comprising compounds (9), (10), (11), (12), (13) and / or (14), ( 20) and / or (21) and / or their enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
- the object of the invention is also achieved by compounds which are selected from the group comprising the general formulas (20) and / or (21) and / or their enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
- These compounds are suitable, for example, for the preparation of medicaments for the treatment of diseases which are influenced by the activity of the guanine nucleotide exchange factors, in particular of the cytohesins, for example autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, diabetes mellitus (Typl), psoriasis, Crohn's disease, allergies, Tumor diseases, such as lung or bronchial cancer, colon or rectal cancer, prostate cancer, lymph or blood cancer, bladder cancer, breast cancer and / or uterine cancer and / or immunosuppression, for example in organ transplantation.
- autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, diabetes mellitus (Typl), psoriasis,
- cytohesins are involved in the activation of integrins.
- compounds selected from the group comprising the general formulas (1), (2), (3), (4), (5), ( 6), (7) and / or (8) are preferably selected from the group comprising compounds (9), (10), (11), (12), (13), (14) and / or (19), (20) and / or (21), for example via an interaction of the cytohesins with integrins, the inhibition of the adhesion of leukocytes to cell surfaces and / or an influence of inflammatory processes, a use of these compounds in the field of medicine in a variety of clinical pictures is made possible.
- an advantage of the compounds provided can be realized by the fact that they can provide a specific inhibitory effect on cytohesin-dependent immune reactions of the cells. Without being bound by theory, it is believed that the compounds provided may provide an inhibitory effect on the adhesion and migration of dendritic cells. Directed migration of dendritic cells is a prerequisite for the development of an adaptive immune response. In preferred embodiments, use of the compounds according to the invention may result in a directed influencing, in particular an inhibition of the adaptive cellular immune response, being able to be provided in cells, tissues and / or organs.
- the compounds provided can, for example, in in vitro experiments show that the adhesion and / or migration of dendritic cells to ICAM-1 (intercellular adhesion molecule-1) can be inhibited even at a lower concentration than needed to have an effect on the Inhibition of insulin-dependent signal transduction cascades.
- ICAM-1 intercellular adhesion molecule-1
- the compounds provided have little or no negligible toxicity, in particular cytotoxicity.
- the compounds provided may have little or no negligible concentration-dependent and / or time-dependent toxicity. This allows the use of the compounds provided for the treatment of human diseases as well as for the production of medicaments.
- a great advantage of the invention is that the compounds selected from the group comprising the general formulas (1), (2), (3) (4), (5), (6), (7) and / or (8 ) preferably selected from the group comprising compounds (9), (10), (11), (12) (13), (14) and / or (19), (20) and / or (21) for the preparation of medicaments are suitable for the treatment of diseases which are influenced by the activity of the guanine nucleotide exchange factors, in particular of the cytohesins.
- These diseases include, for example, diseases in which inflammatory processes play a role, cancer or tumor diseases, allergic diseases, autoimmune diseases and / or diseases in which immunosuppression plays a role.
- Particularly advantageous compounds selected from the group comprising the general formulas (1), (2), (3) (4), (5), (6), (7) and / or (8) are preferably selected from the group comprising Compounds (9), (10), (11), (12) (13), (14) and / or (19), (20) and / or (21) and / or their enantiomers, diastereomers and their pharmaceutically acceptable Salts for the manufacture of a medicament for the treatment of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, diabetes mellitus (Typl), diabetes mellitus (type 2), psoriasis, Crohn's disease, allergies, tumors such as lung or bronchial, colon or rectal cancer, prostate cancer, Lymphoid or blood cancer, bladder cancer, breast cancer and / or uterine cancer and / or immunosuppression, for example, in organ transplantation usable.
- Another object of the invention relates to a method for the identification of compounds which bind to preferably at least one sec7 domain having proteins, the method comprising the following steps: a) producing a fluorescein preferably labeled RNA comprising the steps: aa) optionally Amplification of a DNA sequence bb) optionally purification of the amplified DNA sequence cc) optionally transcription of the DNA sequence into an RNA sequence dd) labeling of the RNA, preferably labeling with fluorescein ee) purification of the labeled RNA b) determination of the polarization of the labeled RNA c) addition of a preferably at least one sec7 domain-containing protein d) determination of the polarization of the complex of protein and labeled RNA e) addition of the compound to be investigated f) determination of the polarization after addition of the compound to be investigated.
- the method is preferably based on the method of fluorescence polarization, wherein an RNA molecule is preferably labeled with a fluorescent marker such as fluorescein.
- the DNA molecule corresponding to the RNA sequence can first be amplified.
- the amplification of a DNA sequence is preferably carried out by PCR reaction.
- the DNA can be worked up and / or purified in a next step, preferably by phenol / chloroform extraction and / or ethanol precipitation.
- the DNA sequence can then be transcribed into an RNA sequence.
- the RNA is tagged with a fluorophore.
- the RNA is transcribed in vitro in the presence of RNA polymerase from phage T7.
- this transcription is carried out in the presence of guanosine 5'-monophosphhothioate.
- Transcription leads to the introduction of a thiophosphate group at the 5 'end of the RNA molecule.
- This thiol group can then react with an activated fluorophore reagent, for example fluorescein or a fluorescein derivative such as 5-iodoacetyl-fluorescein.
- fluorescein-labeled RNA molecules show low polarization.
- polarization is understood to mean in particular a fluorescence polarization.
- the determination of the polarization of the labeled RNA can be carried out in a fluorescence polarimeter.
- a preferably a sec7 domain-containing protein is added.
- Preferred proteins are preferably selected from the group comprising cytohesins such as cytohesin-1, cytohesin-2, cytohesin-3 and / or cytohesin-4, preferably cytohesin-1.
- the protein may be a native cytohesin protein as well as a protein and / or peptide expressed in vitro and purified on a sec7 domain.
- the polarization of the formed complex of protein and labeled RNA increases over that of the free RNA.
- the polarization of the complex of protein and labeled RNA can be determined in a further step of the method. Subsequently, the compound to be examined is added.
- the polarization after addition of the compound to be tested can be measured.
- a compound which binds to the protein can be detected by a decrease in the polarization signal, in particular to the value of the polarization of the free RNA.
- reaction conditions are selected which include RNA in the range from 1 nM to 10 ⁇ M, preferably in the range from 10 nM to 1 ⁇ M, protein in the range from 10 nM to 100 ⁇ M, preferably in the range from 100 nM to 10 ⁇ M, and / or compound to be tested in the range of 1 ⁇ M to 10 mM, preferably in the range of 10 ⁇ M to 1 mM.
- reaction conditions comprising 100 nM RNA, 1 ⁇ M protein and / or 100 ⁇ M of the compound to be investigated.
- the method is useful in advantageous embodiments as a high throughput screening assay. This allows the investigation of a high number of compounds.
- the method has a z-factor, which represents a quality factor for the feasibility of screening methods, of 0.81.
- the DNA and / or RNA sequence is selected from the group comprising M69 aptamers, K61 aptamers and / or natural DNA and / or RNA.
- M69 aptamer which binds the sec7 domain of cytohesin-1 and cytohesin-2 is described, for example, in Mayer, G. et al., Proc Natl Acad. USA 98, 4961-5 (2001).
- K61 aptamer, which specifically binds the sec7 domain of cytohesin-2 is described in Theis, MG et al., Proc Natl Acad Sci USA, 101, 11221-26 (2004).
- aptamers means peptides and / or oligonucleotides which interact specifically with cellular proteins.
- control 2 shows a control experiment with a non-inhibitory compound (control 2) in primary human lymphocytes after stimulation with the monoclonal antibody OKT3
- Fig. 3 shows the DNA sequence of the M69 aptamer, which can be used as a template, as well as the sequence of primers that can be used for amplification
- Fig. 4 shows the inhibitory effect of the compound according to the formula (9) on the adhesion of dendritic cells on the substrate ICAM-I
- Fig. 5 shows the inhibitory effect of the compound according to the formula (9) on the migration of dendritic cells on the substrate ICAM-I
- IC 50 value was determined for the inhibition of the exchange activity of the sec7 domains of various guanine nucleotide exchange factors of the compounds (9), (10), (11), (12), (14) and (19).
- the sec7 domains of cytohesin 1, cytohesin 2 and Gea2 and the N ⁇ 17 ARF1, a mutant of the ARF protein were recombinantly expressed in E. coli BL21DE3, purified by standard procedures and used as catalysts for the exchange of GDP to GTP GTPases of the family of ADP ribosylation factors used.
- the exchange of GDP to GTP induces a conformational change of the ribosylation factor, which increases the fluorescence of a tryptophan residue of the protein.
- the IC 50 value can be determined.
- the IC 50 value corresponds to the concentration of compounds at which the activity of the protein is reduced by half. The lower the IC 50 value, the more the compound inhibits the sec 7 domain.
- Brefeldin A a specific inhibitor of the high molecular weight ADP ribosylation factor Gea2 served as a control.
- the compounds (9), (10), (11), (12), (14) and (19) in particular (9), (10), (11) and (12) show a specific inhibition of the sec7 domains of the cytohesins against the sec7 domain of Gea2, while the reference compound brefeldin A shows a specific inhibition of the sec7 domain of Gea2.
- the IC 50 value was compared to the LC 50 value in a luciferase assay
- HeLa cells according to the experimental conditions described in Theis, M.G. et al., Proc Natl Acad. USA, 101, 11221-26 (2004).
- the stimulation of receptor tyrosine kinases by growth factors contained in fetal calf serum activates the MAPK pathway via cytohesin 2 and results in activation of the serum response element. This activation is reflected in the amount of luciferase produced in the cells.
- LC50 values were determined by an MTT assay according to standard procedures.
- the LC5o value describes the lethal concentration at which 50% of the cells died within 24 hours after a single addition.
- the IC 5 o-value was determined from the plot of the compound concentration versus the intensity of the luciferase signal.
- Human peripheral blood cells were stimulated with agonists that activate beta-2 integrin-dependent adhesion.
- beta-2 integrin-dependent adhesion to its specific ligand ICAM-I can be activated by cytohesins.
- the agonists used were the monoclonal antibody OKT3 (hybridoma of ATCC, mAb OKT3 purified on protein A, according to standard methods of Current Protocols in Immunology, 5th Ed., Coligan et al., Edts, Wiley 2004) against the CD3 complex, a T- ZeIl receptor, and phorbol ester (PMA), the intracellular signaling cascades in human PBL with the inclusion of integrin-dependent adhesion, bypassing cytohesins unphysio strig activated.
- OKT3 hybrida of ATCC, mAb OKT3 purified on protein A, according to standard methods of Current Protocols in Immunology, 5th Ed., Coligan et al., Edts, Wiley 2004
- PMA phorbol ester
- ICAM-1 coated cell culture dishes were prepared by recombinant ICAM-I-Fc fusion protein (Kolanus, W. et al., Cell 86, 233-42 (1996), Geiger, C. et al., EMBO J., 19, 2525 -2536 (2000)).
- the DNA sequence of the M69 aptamer shown in FIG. 3 was amplified by using the primers also shown (SEQ ID NO: 2, SEQ ID NO: 3) by PCR amplified. 0.01 ⁇ M, DNA template, 1 ⁇ M 3 'and 5' primer, 1.5 mM MgC12, 0.2 mM dNTP mix, and Taq polymerase were used.
- the PCR program used consisted of the following steps: denaturation 95 0 C 1 min 15 cycles
- the DNA was subjected to phenol / chloroform extraction according to standard methods and precipitated in ethanol before this monophosphothioate 5 'for 4 hours at 37 0 C in the presence of 20 mM guanosine, T7 RNA polymerase was transcribed. The RNA was then precipitated by ethanol, dissolved in DEPC water and purified on a G25 column (Amersham Biosciences).
- RNA 10 ⁇ M RNA was heated to 95 ° C. with Ix labeling buffer (50 mM Tris, pH 8.0, 5 mM EDTA), 2 M urea and water for 3 min, then allowed to cool for 10 minutes.
- Ix labeling buffer 50 mM Tris, pH 8.0, 5 mM EDTA
- 2 M urea 2 M urea
- water 3 min
- 2.5 mg of activated 5-iodoacetyl-fluorescein were dissolved in 500 ⁇ M DMF and added to the batches.
- the mixture had a concentration of 2 mM 5-iodoacetyl-fluorescein. This mixture was incubated for 2 hours at 37 0 C with gentle shaking under aluminum foil. Subsequently, 3 volumes of 100% ethanol were added, 1/10
- volume 3M NaOAc, pH 5.4 and 1 ul glycogen was added and incubated for 20 minutes at -80 0 C, before centrifuged for 20 minutes at 14000 rpm at 4 0 C. The pellet was washed with 100 ⁇ l 70% ethanol and dissolved in 20 ⁇ l DEPC water.
- RNA was separated in an 8% polyacrylamide gel, the RNA from the gel in 500 .mu.l of 0.3M NaOAc solution for 1.5 hours at 65 0 C eluted, filtered through a glass wool filled syringe, precipitated with ethanol and in Dissolved DEPC water.
- the reaction volume of the fluorescence polarization measurements was 50 ⁇ l of PBS, pH 7.4, 3 mM MgCt.
- the measurements were determined in 384-well plates (Greiner BioOne) in a Polarimeter Type Ultra, TECAN, excitation: 485 nm, emission: 535 nm.
- the z-factor was 0.81.
- the concentrations of the individual measurements were: M69 100 nM
- Dendritic cells were prepared by differentiation factors (IL-4 and GM-CSF) in vitro from blood monocytes isolated from peripheral mononuclear cells (PBMC) by Ficoll density gradient centrifugation from human blood anonymous donors.
- IL-4 and GM-CSF differentiation factors
- PBMC peripheral mononuclear cells
- the blood was diluted 1: 1 with PBS (KCl 0.2 g / l, KH 2 PO 4 0.2 g / l, NaCl 8 g / l, Na 2 HPO 4 1.15 g / l, PAA, Cölbe ) / 2 mM EDTA and layered on half volume of Ficoll. Centrifugation was carried out at 300xg, 30 minutes without brake. After Centrifugation revealed a medium white band containing the PBMC. This was taken up to 50 ml with PBS / 2 mM EDTA and subjected to several washes at 640 ⁇ g, 500 ⁇ g, 400 ⁇ g, 300 ⁇ g and 200 ⁇ g.
- the cells were taken up in a titre of 5 ⁇ 10 6 / ml in "VLE-RPMI + / +" medium (Biochrom, Berlin, containing 10% fetal calf serum (FCS), and 1% penicillin / streptomycin) and incubated for 90 minutes in the incubator at 37 0 C and 5% CO 2 incubated. During this time, the monocytes adhere to the bottom of the culture vessel. Peripheral blood lymphocytes remain in suspension and were removed.
- VLE-RPMI + / + "Biochrom, Berlin, containing 10% fetal calf serum (FCS), and 1% penicillin / streptomycin
- Adherent monocytes were washed 3-4 times with PBS and taken up in "VLE-RPMI + / +" medium containing 20ng / ml each of the human recombinant cytokines IL-4 and GM-CSF (Granulocyte Macrophage-Colony Stimulating Factor, R & D
- the quantitative analysis of the cell migration was carried out in modified Boy den chambers consisting of a 24-well plate in which Transwell® filters with a pore size of 5 ⁇ m were used.
- the modified Boy den- chambers thus contained a chamber above the filter and a chamber below the filter.
- the filters were coated with supernatants of ICAM-I secreting fibroblasts.
- Mature dendritic cells were incubated for 96 hours with 1 ⁇ M, 10 ⁇ M or 15 ⁇ M of the compound of formula (9) in "VLE-RPMI + / +" medium. All approaches contained 0.5% DMSO. Controls contained only 0.5% DMSO without the compound of formula (9).
- adhesion was determined after stimulation with phorbol ester (PMA, 50ng / ml, Sigma, Taufkirchen) or anti-beta-2 integrin antibody MEM-48 (5 ⁇ g / ml, Vaclav Horeijsi, Czech Academy of Sciences Prague).
- PMA phorbol ester
- MEM-48 anti-beta-2 integrin antibody
- control in each case was the migration of cells not treated with the compound of the formula (9) after stimulation with the chemokines CCL19 or CXCL12 or the adhesion of cells not treated with the compound of the formula (9)
- PI propidium iodide
- Peripheral blood lymphocytes were incubated at concentrations of 50 nM, 100 nM, 1 ⁇ M, 5 ⁇ M, 20 ⁇ M or 50 ⁇ M of the compound according to formula (9) in "VLE-RPMI + / +" (biochrome) Concentration per batch was 0.5%, one control batch containing 0.5% DMSO After 2 hours, 24 hours and 72 hours cells were removed and incubated with 2 ⁇ g / ml PI for 5 minutes Cells were incubated at 200xg, 8 minutes centrifuged, washed with PBS, centrifuged again and analyzed in a flow cytometer (Beckmann Coulter, Krefeld).
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DE102004055998A DE102004055998A1 (de) | 2004-11-19 | 2004-11-19 | Niedermolekulare Inhibitoren von Guaninnucleotid-Austauschfaktoren der Cytohesin-Familie |
PCT/EP2005/056084 WO2006053903A2 (de) | 2004-11-19 | 2005-11-18 | Niedermolekulare inhibitoren von guaninnucleotid-austauschfaktoren der cytohesin-familie |
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WO2009117365A2 (en) | 2008-03-17 | 2009-09-24 | Northwestern University | Vaccine compositons for inducing immune responses against components of drusen |
BRPI0903901A2 (pt) * | 2008-04-16 | 2017-05-23 | Univ Of Utah Res Foudation | composição, métodos para inibir permeabilidade vascular, angiogênese patológica, e um mais de ativação ou disponibilidade de rac, ativação ou disponibilidade de arf6, vazamento vascular, permeabilidade vascular, angiogênese patológica e inibição de sinalde múltiplos fatores angiogênicos, de permeabilidadee inflamatórios, e, métodos para preservação de função de barreira endotelial, e para bloqueio de sinalização de vegf a jusante do receptor de vegf |
EP2286808A1 (de) | 2009-08-18 | 2011-02-23 | Rheinische Friedrich-Wilhelms Universität | Cytohesininhibitoren |
WO2014145314A2 (en) | 2013-03-15 | 2014-09-18 | Cancer Research Technology, Llc | Methods and compositions for gamma-glutamyl cycle modulation |
AU2015308350B2 (en) | 2014-08-29 | 2020-03-05 | Tes Pharma S.R.L. | Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase |
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