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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
• • 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
  • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • 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
  • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0031—Rectum, anus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0046—Ear
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • 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
• • 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
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/12—Mucolytics
• • 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
• • 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

Definitions

• the present invention relates to the use of glucosidase inhibitors for the preparation of medicaments for the treatment of cystic fibrosis.
• Cystic fibrosis (CF: Cystic Fibrosis) is the most common recessive genetic, autosomal, and lethal disease in European and North American populations.
• the CF gene (locus 7q31) codes for the trans-membrane protein named CFTR (for Cystic Fibrosis Transmembrane Conductance Regulator) (Tsui et al., 1985, Riordan et al., 1989).
• Mutations in the CF gene cause abnormal transport of water and electrolytes across cell membranes of various organs such as the lungs, sweat glands, intestine and exocrine pancreas.
• mutations of the CFTR protein Although there are more than 1000 mutations of the CFTR protein, the most common mutation (70% of patients) is the deletion of phenylalanine in the NBF1 domain at position 508 (delF508).
• the main cause of death in CF patients is related to this deletion and leads to infections or pulmonary insufficiency caused by an increase in mucus viscosity. This viscosity causes occlusion of the airways and favors infections by opportunistic bacteria.
• An aggravation is moreover noted at the digestive level and in particular pancreatic (pancreatic-insufficient patient).
• the CFTR protein is a 1480 amino acid glycoprotein belonging to the super-family of ABC membrane transporters, CFTR is a chloride channel located in the apical plasma membrane of pulmonary epithelial cells in healthy individuals.” CFTR is responsible for transepithelial transport of In healthy CF patients, this protein is absent from the plasma membranes due to a poor targeting of the protein that is retained in the endoplasmic reticulum (ER). The hydration of the pulmonary airways is no longer functional in this case delF508 deletion disrupts the folding of the NBF1 domain and prevents the complete maturation of the protein, which is therefore degraded very early during its biosynthesis.
• the delF508 protein reaches the membrane, it functions as a chloride channel, one of the keys to This disease therefore consists of a re-addressing of delF508 to the cell membrane.
• delF508 transport activity can be stimulated by endogenous or exogenous physiological agonists.
• the mechanism of addressing the CFTR protein is as follows. After its neosynthesis, the CFTR protein is found in ER light where it undergoes various glycosylations through glycosyl transferases. The protein is found with, among other things, 3 N-linked glucoses and 1 mannose.
• glucosidase I and IL Calnexin or calreticulin, calcium dependent chaperones recognize the monoglucosylated protein and bind to it via N-linked glucose. These chaperones avoid the different CFTR proteins. present in the ER to aggregate together and allow the attachment of other chaperones such as ERp57. The CFTR / Calnexin / ERp57 complex thus formed allows folding of the CFTR. Then, glucosidase II removes the remaining glucose, releasing the CFTR from the chaperones.
• a glucosyltransferase adds a glucose to the CFTR which can again undergo one or more cycles until it is well folded. If the folding is still incorrect, a mannosidase removes the N-linked mannose, the protein will then be transported in the cytosol, via the translocon channel complex, where it can be degraded (Ellgard & Helenius, 2003). This phenomenon is observed for 80% of CFTR-WT and 99% of delF508-CFTR. Once in the cytosol, the protein is supported by different chaperones such as Hsp70, Hsp90 or Hdj-2. These chaperones allow ubiquitin to attach to the CFTR.
• CFTR is recognized and degraded by the 26S proteasome complex that is ATP-dependent (Gelman et al., 2002). If the CFTR refolding is considered correct by the reticulum control machinery, the protein can reach the Golgi apparatus. It will be supported by the cargo protein ERGIC-53 (belonging to the lectin family) which binds to CFTR via mannose. Crossing ERGIC is via vesicles formed by COP I factor (Ellgard & Helenius, 2003).
• NB-DNJ N-Butyl-deoxynojirimycin
• This molecule also called OGT 918, has been studied in the treatment of Gaucher disease (Dwek et al., 2000, Cox et al, 2000).
• This genetic disease is due to a lysosomal enzyme deficiency, ⁇ -glucocerebrosidase, which causes glucocerebroside accumulation (substrate of the enzyme).
• NB-DNJ a glucosyltransferase inhibitor involved in glucocerebroside biosynthesis, thus prevents their synthesis and accumulation (Dwek et al, 2000, Cox et al, 2000).
• NB-DNJ obtained the Marketing Authorization as a medicine in Gaucher disease under the name Zavesca® in 2002.
• the present invention stems from the discovery by the inventors that NB-DNJ and other inhibitors glucosidase in general, are able to restore delF508 membrane addressing without altering other chloride channels, and allow delF508 to function as an ion carrier.
• the present invention relates to the use of glucosidase inhibiting compounds for the preparation of a medicament for the treatment of cystic fibrosis.
• glucosidase inhibitor is meant any glucosidase inhibitor 'I and / or II, inhibition of these glucosidases that can be measured in particular using the method described in Platt et al, 1994.
• the present invention relates more particularly to the above-mentioned use of glucosidase inhibiting compounds, said compounds being selected from those capable of restoring delF508 membrane addressing without altering other chloride channels, and allow delF508 to function as an ionic transporter, especially in the framework of experiments described hereinafter performed on pulmonary human CF15 epithelial cells homozygous for delF508 deletion.
• the subject of the invention is more particularly the aforementioned use of glucosidase inhibiting compounds chosen from the compounds of the following general formula (I):
• - R 1 represents a CH 3 group, or CH 2 OH
• - R 2 represents H or an alkyl group of 1 to 5 carbon atoms, - or R 1 and R 2 together with the carbon in position (a) and the nitrogen of the formula
• the invention relates more particularly to the above-mentioned use of the following compounds of formula (I):
• DNJ deoxynojirimycin
• DFJ deoxyfuconojirimycin
• DMJ deoxymannojirimycin
• glucosidase inhibitors chosen from the compounds of general formula (II) below:
• R 2 represents H or an alkyl group of 1 to 5 carbon atoms.
• the subject of the invention is more particularly the aforementioned use of glucosidase inhibitors as defined above, chosen from the compounds of general formula (Ubis) below:
• the invention also relates to the aforementioned use of glucosidase inhibitors according to one of claims 1 to 4, chosen from the following compounds of general formulas (11.1) or (13.2): wherein R 2 represents H or an alkyl group of 1 to 5 carbon atoms.
• the invention relates more particularly to the above-mentioned use of compounds of formulas (11.1) or (II.2) as defined above in which R 2 represents H or an N-butyl group as follows:
• NB-DNJ N-butyldeoxynoylimycin
• NB-DMJ N-butyldeoxymannojirimycin
• the compounds used in the context of the present invention are NB-DNJ and NB-DMJ. More preferably, the compound used in the context of the present invention is the
• glucosidase inhibiting compounds defined above, for the preparation of an orally administrable drug (syrup, suspension, capsule, tablet, powder or granule), rectal (suppository), nasal
• the invention also relates to the above-mentioned use of glucosidase inhibitor compounds defined above in combination with a CFTR channel activator compound.
• the subject of the invention is more particularly the aforementioned use of glucosidase inhibitor compounds defined above in combination with a CFTR channel activator compound chosen from: the genistein of the following formula:
• R 1 and R 2 represent a hydrogen atom, or form, in combination with C 1 and C 2, an aromatic ring with 6 carbon atoms
• R 5 represents a hydrogen atom, or a linear or substituted alkyl group from 1 to
• R' represents a linear or substituted alkyl group of 1 to 10 carbon atoms, especially an ethyl group
• - Y represents a group -OH, - SH, -NH2, or -NHCOCH3, -R7, R8, R9 and RJO represent a hydrogen atom, or at least one of R7, R8, R9 or Rio, represents a halogen atom, especially an atom of chlorine, bromine or fluorine
• X represents a halogen atom in anionic form, in particular a bromine atom Br ", or chlorine Cl", or a group of atoms in anionic form.
• the invention more particularly relates to the above-mentioned use of glucosidase inhibitor compounds defined above in combination with benzo [c] quinolizinium derivatives of formula (II) chosen from the following compounds: compound 13 (MPB-01) compound 11 (MPB-26)
• the subject of the invention is also the products comprising at least one glucosidase inhibiting compound, in particular a compound of formula (I) or (II) as defined above, and at least one activating compound of the CFTR channel as defined herein. above, as combination products for simultaneous, separate or spread over time use in cystic fibrosis therapy.
• the invention will be further illustrated by the following detailed description of the experimental demonstration of the correct and specific addressing effect of delF508 by MB-DNJ, without the latter affecting its ion transporter activity as well. cell viability. D MATERIAL AND METHODS Ml.
• CHO-WT Cells CHO (Chinese Hamster Ovary) cells are fibroblasts that have been transfected with the wild-type CFTR gene (CFTR-WT). These cells will therefore overexpress the CFTR protein.
• Culture medium MEM alpha medium (GIBCO) + 7% fetal calf serum + 0.5% penicillin / streptomycin + 100 ⁇ M methothrexate (Amethopterin, Sigma)
• CF15 cells CF15 cells are human epithelial cells of nasal origin that express the ⁇ F508-CFTR gene.
• Culture medium Medium DMEM + HAM F12 + 10% FCS + 0.6% penicillin / streptomycin + growth factors (insulin 5 ⁇ g / ml, transferrin 5 ⁇ g / ml, epinephrine 5.5 ⁇ M, adenine 0.18 mM, 10 ng / ml EGF, 2 nM T3, 1.1 ⁇ M Hydrocortisone)
• Calu-3 cells Calu-3 cells are human lung epithelial cells that express the wild-type CFTR gene.
• Culture medium DMEM / F12 medium with glutamax + 7% fetal calf serum + 1% penicillin / streptomycin M2.
• Immunolabeling allows to visualize the cellular localization of the CFTR protein by means of a primary anti-CFTR antibody (Ac) and then a Cy3 fluorophore-labeled secondary antibody anti-primary antibody.
• the cells are first seeded on slides in appropriate culture medium. 3 washings with TBS (NaCl: 157 mM, Tris base: 20 ⁇ M, pH 7.4) of 5 min each are carried out. The cells are then fixed by adding
• TBS-paraformaldehyde (3%) for 20 min. After 3 washes with TBS (5 min), the cells are incubated with 0.1% TBS-triton (10 min) which allows the formation of holes in the cell membrane, then 3 TBS washes are again performed before the setting in the presence of cells with 0.5% TBS-BSA-0.05% saponin for 1 h. The cells are then incubated with the CFTR anti-C terminal primary antibody (2 ⁇ g / ml) for 1 h. 3 washings with TBS-BSA-saponin of 5 min each are carried out before incubation with the secondary antibody GAM-cy3 (1/400) for 1 h.
• the tracer ( 125 I) is incorporated into the intracellular medium. Then, the amount of radiotracer that leaves the cell is counted after the addition of different pharmacological agents. Iodide is used as a tracer of chloride ion transport. It has been shown that the two radiotracers 125 I and 36 C1 could be considered as equivalent for the measurement of the activity of a channel chloride (Venglarick et al, 1990). In addition, it has the advantage of having a short life compared to that of 35 C1 (1/2 life respectively: 30 days and 300000 years). The cells are cultured on 24-well plates in a suitable medium.
• the cells are incubated with 500 ⁇ l of loading (l ⁇ Ci / ml of 125 INa) for 30 min for CHO-WT or 1 hour for CF15 and Calu-3. Iodide equilibrates on both sides of the cell membrane.
• the robot (MultiPROBE, Packard) performs the following steps: The charge medium is rinsed with efflux medium to eliminate extracellular radioactivity. The supernatant is collected every minute in hemolysis tubes and the medium is replaced by an equivalent volume (500 ⁇ l). Samples of the first 3 minutes do not undergo the addition of drugs, they allow to obtain a stable baseline, characterizing the passive output of the T ions. The following 7 samples are obtained in the presence of the test molecule.
• the cells are lysed by adding 500 ⁇ l of NaOH (0.1 N) / 0.1% SDS (30 min), thus, the radioactivity remaining inside the cell can be determined.
• the radioactivity present in the hemolysis tubes is counted in counts per minute (cpm) by means of a gamma counter (Cobra H, Packard).
• This iodide stream is represented as a curve.
• Relative speed (min -1 ) Rpic - Rbasal.
• the MTT toxicity test is a colorimetric test based on the ability of mitochondrial dehydrogenases to metabolize MTT (yellow tetrazolium salt) to formazan (purple). The absorbance, proportional to the converted dye concentration, can then be measured spectrophotometrically.
• the cells are incubated on 96-well plates in the presence of the agent to be tested for 2 hours. 3 controls are performed: 100% living cells: cells without agents; 0% living cells: cells left in the open air; white: medium without cell.
• the cells are rinsed with RPMI medium without phenol red so that the color of the medium does not interfere with the absorbance measurements.
• the third control corresponds to cells treated with MPB-91 2h at 37 ° C. and then stimulated with 250 ⁇ M MPB-91.
• the CFTR activity in this experimental condition is not significantly different from the other two experimental situations.
• the Calu-3 cells are treated for 2 h at 37 ° C. with 500 ⁇ M NB-DNJ and stimulated with 250 ⁇ M MPB-91, the level of CFTR activity is not affected.
• NB-DNJ causing an accumulation of delF508 in the endoplasmic reticulum allows a membrane re-localization of this protein and therefore represents an important pharmacological means of re-addressing delF508 in an epithelial cell.
• pulmonary human NB-DNJ allows the specific membrane addressing of delF508 without affecting the ion transporter activity of this protein, and has no effect on other chloride channels, nor on cell viability.
• FIGURE LEGEND Figure 1 Effect of NB-DNJ on delF508 addressing.
• the CF15 cells were pre-treated for 2 h with NB-DNJ (500 ⁇ M).
• the effect of MPB-91 (250 ⁇ M) is considered to represent 100% in this test.
• Ns not significant difference ***: significant difference PO.001
• Figure 2 NB-DNJ effect curve on delF508 addressing.
• CF15 cells were pre-treated for 2h with NB-DNJ at different concentrations.
• Figure 3 Effect of NB-DNJ on the anionic transport of Calu-3 cells.
• fsk and MPB-91 activate an iodide efflux in this cell, but not the NB-DNJ which has no effect.
• Ns not significant difference ***: significant difference P ⁇ 0.001
• Figure 4 Effect of NB-DNJ treatment of Calu-3 cells.
• the Calu-3 cells are pre-incubated for 2 h at 37 ° with 500 ⁇ M NB-DNJ, with MPB-91 250 ⁇ M.
• Untreated cells no treat.
• the basal indicates that the cells have not been treated or stimulated.
• Figure 5 Effect of NB-DNJ on the cytotoxicity of CHO cells. Note that at 5 and 50 ⁇ M no cytotoxicity is measurable.

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