WO1992016226A1 - Inhibiteurs d'il-1 - Google Patents

Inhibiteurs d'il-1 Download PDF

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Publication number
WO1992016226A1
WO1992016226A1 PCT/US1992/002214 US9202214W WO9216226A1 WO 1992016226 A1 WO1992016226 A1 WO 1992016226A1 US 9202214 W US9202214 W US 9202214W WO 9216226 A1 WO9216226 A1 WO 9216226A1
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inhibitor
cells
cyclosporin
glycoprotein
disease
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PCT/US1992/002214
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English (en)
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Philip A. Krasney
Peter Ronald Young
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Smithkline Beecham Corporation
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Publication of WO1992016226A1 publication Critical patent/WO1992016226A1/fr

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • 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
    • 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
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/49—Cinchonan derivatives, e.g. quinine
    • 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
    • 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
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/545—IL-1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C07K14/7155—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for interleukins [IL]

Definitions

  • This invention relates to a novel mechanism for inhibition of Interleukin - 1 (hereinafter IL-1) synthesis and hence treatment-of disease states in a mammal caused by or exacerbated by IL-1 production.
  • IL-1 Interleukin - 1
  • Interleukin-1 is the name given to a. family of secreted proteins which have numerous pro-inflammatory properties. These include the stimulation of prostoglandins, endogenous pyrogenic activity, stimulation of immune cell functions, induction of degradative enzymes such as stromelysin, collagenase and various neutral proteases, and induction of other cytokines. These activities are associated with numerous inflammatory conditions, such as rheumatoid arthritis and inflammatory bowel disease, inter alia, thus implicating IL-1 as a major target for therapeutic interventio .
  • This invention relates to a method of treating an IL-1 mediated disease state in a mammal in need thereof by administering to said mammal an effective amount of an inhibitor of mammalian mdr P-glycoprotein mediated IL-1 secretion, provided that the inhibitor is not a steroid or hormonal analog.
  • IL-l ⁇ There are presently known to be three members of the IL-1 family, IL-l ⁇ , IL-l ⁇ and IL-lra.
  • Il-i ⁇ and IL-l ⁇ are active moieties and are able to bind to receptors on target cells.
  • IL-lra does not have activity and yet has comparable affinity to the same receptors, indicating that it is a natural receptor antagonist to IL-l ⁇ and IL-l ⁇ .
  • the major source of IL-1 activity is the monocyte- acrophage cell, and the major form secreted is IL-l ⁇ .
  • Il-l ⁇ and IL-l ⁇ are synthesized as 31 kDa precurser molecules which are subsequently cleaved to active, mature, carboxy terminal fragments upon release. Secretion of both precursors and mature forms has been observed, and yet precursor IL-l ⁇ is inactive, whereas precursor IL-l ⁇ is active.
  • the bacterial and yeast P-glycoproteins are somewhat similar to a series of mammalian P-glycoproteins originally identified for their ability to confer multidrug resistance when overexpressed in the host cell.
  • Multidrug resistance is a clinically important obstruction to long term cancer treatment. Tumors treated with one form of chemotherapeutic agent often arise later in a resistant form. It has been observed that these tumor cells are not only resistant to the original drug, but also to other non-structurally related chemotherapeutic agents, thus restricting the available drugs to keep the disease in check.
  • This resistance phenotype has been observed in vitro with cell lines, and has been shown to be conferred by amplification of the multi-drug-nesistance gene (hereinafter referred to as mdr) and overexpression of its P-glycoprotein product. Cloning has indicated that there are two highly related mdr genes in man, three in rodents, and at least one of the mdrl genes has clearly been associated with multi drug resistance. P-glycoprotein seem to function by "pumping" the toxic drugs out of the cells, thus maintaining a lower concentration within the cells.
  • mdr multi-drug-nesistance gene
  • calcium antagonists such as but not limited to, verapamil, verapamil analogs, desmethoxyverapamil, dilitiazem, nifedipine, nifedipine analogs: tiapamil, DMDP, nicardapine, diludapine, nimodipine; dihyropyridine analogs, caroverine, prenylamine, bepridil, AHC-52, Roll-2933, perhexiline maleate, or SDB-ethylendiamine;
  • verapamil verapamil analogs
  • desmethoxyverapamil dilitiazem
  • nifedipine nifedipine analogs: tiapamil, DMDP, nicardapine, diludapine, nimodipine
  • dihyropyridine analogs caroverine, prenylamine, bepridil, AHC-52, Roll-
  • calmodulin antagonist such as but not limited to, the phenothiazine derivatives: trifluoperazine, thioridazine, chlorpromazine, prochlorperazine, trifluropromazine, perphenazine, chlomiperamine, fluphenazine, flupenthixol, chlorprothiexene, clolpenthixol, W-12 or -13.
  • noncytotoxic anthracyclines Vinca alkaloids or Vinca alkaloid analog, such as but not limited to, ID-8279, Vindoline, daunorubicin, doxorubicin, cepharanthine, or aclacinomyin A;
  • cyclosporins such as but not limited to, Cyclosporin A, Cyclosporin C, Cyclosporin G, Cyclosporin H, 11-Me-Ile (W8-032), O-Acetyl Cg, 11-Me-Leu, or 6-Me-Ala;
  • hydrophobic cationic compounds which are amphipathic and lipophillic nature, contain a broad structural similarity that includes a heterocyclic ring nucleus seperated at a distance from a cationic, amino group; such as but not limited to dipyridamole, quinacrine, primaquine, quinidine, quinine, amiodarone, indole alkaloids - reserpine, rescinnamine, yohimibine, trimethoxybenzoyl- yohimibine; alkaloid derivatives of cepharanthine, lysosomotropic amines- chloroquine,propranol; erythromycin, cefoperazone, ceftriaxone, and triparanol, . .
  • Calmodulin antagonists as used herein are meant to include a group of anti-mdr agents which possess the ability to inhibit CaM-mediated processes, such as the Ca+2/CaM-dependent form of cyclic nucleotide phosphodiesterase.
  • CaM-mediated processes such as the Ca+2/CaM-dependent form of cyclic nucleotide phosphodiesterase.
  • calmodiulin antagonists are the phenothiazine derivatives.
  • steroid or hormonal analogs agents which are generally referred to as a steroid, i.e. possesing a steriod ring nucleus and those hormonal analogs which posses antiestrogen activity, such as tamoxifen, toremifene structurally related triparanol analogs, which are referred to in Ford et al., Pharm. Reviews. Vol.42, No. 3 (1990) pages 155-199, specifically 168-173 inclusive.Ford et al., Pharm. Reviews,. Vol.42, No. 3 (1990) pages 155-199, specifically p 173 inclusive.
  • the method of this invention may also include using an inhibitor of the P-glycoprotein IL-1 secretion as defined herein, co-administered with a steroid or hormonal analog.
  • IL-1 is a protein which is both produced and secreted.
  • the present invention provides for a method of inhibiting the secretion of IL-1 by compounds which are inhibitors of the mammalian mdr P-glycoprotein "pump".
  • interleukin - l ⁇ is a protein which lacks weak hydrophobic sequence signals which are generally expected to be present to allow for translocation into the endoplasmic reticulum (ER) and thereby secretion by the usual pathway.
  • ER endoplasmic reticulum
  • previous work has indicated that these proteins are not translocated into the ER.
  • the present invention demonstrates that the P-glycoprotein moiety is involved in active transport of IL-1 and inhibition of the mdr "pump" by an agent, would clearly provide a means for prophylactically treating, or ameliorating IL-1 mediated disease states, particularly those disease states which are strongly inflammatory oriented, such as arthritis.
  • the present invention is a method for treating an inflammatory disease which is mediated by IL-1 , in a mammal, including humans, with any compound capable of inhibiting the mdr P-glycoprotein and is administered in an amount sufficient to inhibit the P-glyco ⁇ protein.
  • Interleukin-1 has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions such as inflammation [See, e.g., Dinarello et al., Rev. Infect. Disease. £, 51 (1984)].
  • the myriad of known biological activities of IL-1 include the activation of T helper cells, induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute phase proteins and the suppression of plasma iron levels.
  • This invention further relates to the use of a compound as defined by this invention, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of prophylactically or therapeutically, any disease state in an animal, including humans, which is exacerbated or caused by excessive or unregulated IL-1 production by inhibition of mammalian mdr P-glycoprotein IL-1 secretion.
  • mdr P-glycoprotein as used herein is meant the naturally occuring P-glycoprotein moiety produced by any multi-drug-resistance genes, any variant or homolog thereof, as well as functional equivalents thereof which may or may not confer mdr to the host cells.
  • mdrl At present only two mdr genes are known, and are generally referred to as mdrl and mdr3.
  • the P- glycoprotein inhibited is the mdrl expressed P-glycoprotein.
  • P-glycoprotein One skilled in the art can readily determine whether or not a P-glycoprotein is functionally equivalent by recognized assays used to determine multi-drug resistance for instance the chemotherapeutic agents used for cancer chemotherapy.
  • assays would include indicators such as decreased sensitivity to a particular drug by the cell in the presence of overexpressed mdr and/or an ability of the cell to increase the toxic levels of a drug by reducing the intracellular levels of that drug.
  • indicators such as decreased sensitivity to a particular drug by the cell in the presence of overexpressed mdr and/or an ability of the cell to increase the toxic levels of a drug by reducing the intracellular levels of that drug.
  • Such assays can be found, for instance in, van Der Collins, et al., EMBO J. 6:3325-31 (1987) whose disclosure is incorporated by reference herein. See also Ford, et al., Pharmacology of drugs that alter multidrug resistance in cancer. Pharm. Rev. 42: 155-199 (1990), and Endicott et al., Annu Rev. Biochem.. 58:137-71 (1989) .
  • inhibiting the production of IL-1 is generally meant a) a down regulation, by inhibition of the direct synthesis of IL-1 as a postranslational event; or b) a decrease of excessive in. vivo IL-1 levels in a human to normal levels or below normal levels by inhibition of the in vivo release of IL-1 by all cells, including but not limited to, monocytes or macrophages; or but least preferred is c) a down regulation, at the transcription or translational level, of excessive in vivo IL-1 levels in a human to normal levels or below normal levels.
  • IL-1 mediated disease or disease state any and all disease states in which IL-1 plays a role, either by production of IL-1 itself, or by IL-1 causing another monokine in the cytokine cascade to be released, such as but not limited to TNF, or IL-6.
  • TNF for instance is a major component, and whose production or action, is exacerbated or secreted in response to IL-1, would therefore be considered a disease mediated by IL-1.
  • monokine is generally referred to as being a polypeptide produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte but many other cells produce monokines, such as natural killer cells, fibroblasts, basophils, neutraphils, endothelial cells, brain astrocytes, bone marrow stromal cells, epideral keratinocytes, and ⁇ - lymphocytes. Lymphokines are generally referred to as being produced by lymphoctye cells.
  • IL-1 interfering or suppresive amount an effective amount of a compound of this invention which will, when given for the treatment, prophylactically or therapeutically, of any disease state which is exacerbated or caused by excessive or unregulated cytokine production, cause a decrease the in vivo levels of IL-1 or other cytokines/monokines, to normal or below normal levels.
  • This invention also relates to the use of a pharmaceutical composition for use in treating an IL-1 mediated disease, comprising an effective amount of an inhibitor of P-glycoprotein , a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutical composition for use in treating an IL-1 mediated disease comprising an effective amount of an inhibitor of P-glycoprotein , a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
  • the compounds used in the process of this invention can be administered in conventional dosage forms prepared by combining an inhibitor as defined herein, with standard pharmaceutical carriers according to conventional procedures.
  • a wide variety of pharmaceutical dosage forms can be employed.
  • the route of administration will depend upon the particular inhibitor chosen. It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
  • the methods of the subject invention may be carried out by delivering the monokine activity interfering agent by various routes of administration , and includes such routes as oral, pulmonary, parenteral, buccal, intra-articular, nasal or topical.
  • routes of administration includes such routes as oral, pulmonary, parenteral, buccal, intra-articular, nasal or topical.
  • the 'term 'parenteral' as used herein includes intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration. Subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • an inhibitor as disclosed herein required for therapeutic effect upon administration will, of course, vary with the compound chosen, the nature and severity of the inflammatory condition, the mammal undergoing treatment, and is ultimately at the discretion of the physician. It will also be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of an inhibitor of the present invention , or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques.
  • the optimal course of treatment i.e., the number of doses of an inhibitor of the present invention or a pharma ⁇ ceutically acceptable salts thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • the present invention demonstrates that human mdrl and mdr3 are involved in IL-1 secretion.
  • the following assay, described below, uses COS (monkey kidney) cells co- transfected with DNA vectors encoding various combinations of precursor or mature IL-l ⁇ and human mdrl or mdr3. In the absence of mdr, precursor and mature IL-l ⁇ are not secreted. In the presence of mdrl, mature IL-l ⁇ is secreted and pre ⁇ cursor IL-l ⁇ is not. Human mdr3 is shows a small amount of secretion relative to the control and to mdrl.
  • Peripheral blood monocytic cells were obtained after isolation from Red Cross buffy coats. The isolation procedure consisted of sequential Lymphoprep (Nyegaard, Oslo, Norway) and Percoll (Pharmacia) gradient centrifugation as described in Colatta et al., 1985. Purified monocytes were plated onto 100 cm 2 tissue culture dishes and allowed to adhere in the presence of RPMI (GIBCO) + 1% human AB serum (MA Bioproducts, Walkersville, MD) + 100 ng/ml bacterial lipopolysaccharide (£__. coli 055:B5, Difco, Detroit, MI) . One hour after plating, LPS-stimulated monocytic cells were etabolically labeled according to the protocol described belo . - ⁇ 3 -
  • COS cells were maintained at 37 °C / 5% CO 2 in Dulbecco's Modified Eagle Medium (DMEM) containing 10% fetal bovine serum (FBS) , 10 u/ml penicillin, 10 mg/ml streptomycin and 25 ng/ml amphotericin B. All tissue culture media and supplements, except where indicated, were supplied by GIBCO.
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS fetal bovine serum
  • Transfection for transient expression in COS cells was carried out by a DEAE-dextran/chloroquine protocol.
  • Cells were seeded on 100 cm 2 culture plates at 1.5 X 10 6 cells per plate 16 - 24 h before transfection.
  • cells were washed with phosphate buffered saline (PBS; 137 mM NaCl, 2.7 mM KC1, 1.3 M KH 2 PO 4 , 9.5 MM Na 2 HP0 ) and incubated for 1 h in 2.5 ml of DMEM containing 10% NuSerum (Collaborative Research, Lexington, MA) .
  • PBS phosphate buffered saline
  • Cesium chloride gradient-purified plasmid DNA (20 mg per plasmid per transfection) was resuspended in 0.5 ml of Tris buffered saline (TBS; 137 mM NaCl, 5 mM KC1, 1.5 mM Na 2 HP0 4 , 250 mM Tris-HCl, pH 7.5, 1.4 mM CaCl 2 , 1.1 mM MgCl ) before it was added to 2 ml of DMEM containing 1 mg/ml DEAE-dextran (Pharmacia) and 1 mg/ml chloroquine (Sigma). The 2.5 ml of transfection mixture was then added to the 2.5 ml of DMEM/NuSerum on the cells.
  • TBS Tris buffered saline
  • the cells were incubated 2.5 h in the presence of the transfection mixture before being washed with PBS, shocked with 10% DMSO in PBS for 3 min, washed again with PBS and incubated 42 - 48 h in DMEM/10% FBS/antibiotics/antimycotic as described above. Mock transfectants were generated as above, but in the absence of exogenous DNA.
  • Transfectants 42 - 48 h post-DMSO shock were washed with PBS before depleting them of internal cysteine and methionine pools by incubating them for 1 h in cysteine- and methionine- deficient DMEM containing 1% dialyzed FBS (dFBS) .
  • Cells were then radiolabeled by incubating them with fresh cysteine- and methionine-deficient DMEM/1% dFBS (dialyzed FBS) containing 150 mCi/ml (with respect to ethionine) Tran 35 S-label (ICN) for 1 h.
  • Secreted products were allowed to accumulate in chase medium (DMEM/1% FBS) for various times following the labeling period.
  • LPS-stimulated monocytic cells (1 h post-plating) were labeled and treated similarly, except that 100 ng/ml LPS was present at all times.
  • Labeled cells were harvested by removing the media, washing with PBS and lysing on the plate with 1 ml of RIPA buffer (150 mM NaCl, 10 mM Tris-HCl, pH 7.5, 1% deoxycholate, 1% Triton X-100, 0.1% SDS, 10 mM EDTA, 2 mM PMSF) . Sample aliquots were cleared prior to immunoprecipitation by making them IX RIPA/2% Carnation milk (lysate samples) or 0.5X RIPA/0.5% milk (media samples) and rotating them for 0.5 h at 4 °C after adding 15 ⁇ l of half-packed Protein A - Sepharose 4B beads (Pharmacia) .
  • RIPA buffer 150 mM NaCl, 10 mM Tris-HCl, pH 7.5, 1% deoxycholate, 1% Triton X-100, 0.1% SDS, 10 mM EDTA, 2 mM PMSF
  • Immune complexes were recovered by adding 50 ml of half- packed Protein A - Sepharose 4B beads to the samples, rotating the samples for 1 h at 4 °C and pelleting the beads as described above. The beads were washed three times with IX RIPA buffer before resuspending them in either 50 ml of SDS-PAGE gel loading buffer (62.5 mM Tris-HCl, pH 6.8, 1% SDS, 8% glycerol, 1.2 M b-mercaptoethanol, 0.1% bromphenol blue) .
  • SDS-PAGE gel loading buffer 62.5 mM Tris-HCl, pH 6.8, 1% SDS, 8% glycerol, 1.2 M b-mercaptoethanol, 0.1% bromphenol blue
  • RSVILlb Precursor and RSVILlb Mature were constructed from RSVCATBGH by deleting the 726 bp Hind III Xba I fragment containing the bacterial chloramphenicol acetyl-transferase gene and replacing it with either the 950 bp Hind III- partial/Xba I fragment of DSPIL-l ⁇ precursor (Young et al.,
  • DSPIL-l ⁇ mature was generated by ligating the 1.1 kb Nco I/Xba I fragment of pMGNcoIL-l ⁇ into DSP1 (Seeffleffle et al..DNA 4:461-467 1985;
  • the plasmid directing the expression of human ATP citrate lyase, HCL- RJB2 can be readily constructed by one skilled in the art using the literature references of Elshourbagy et al.. 1990, J.Biol Chem.
  • COS cells transfected with RSVILlb Mature or co- transfected with RSVILlb Mature and either pJ3Wmdrl.1 or pJ3Wmdr3 were split 1:1 onto fresh 100 cm 2 tissue culture plates immediately following trypsinization one day after transfection.
  • one plate of each sample (approximately lxlO 6 cells) was metabolically labeled and immunoprecipitated with antiserum S32 to assess mature IL-l ⁇ production and secretion as described above.
  • the parallel samples representing the remaining half of the cells replated the previous day, were washed once with PBS before doping for 20 min with 5mCi of 3 H-vinblastine sulphate (Amersham) in 4 ml of DMEM/1% FBS. Cells were then washed twice in PBS before incubating for 20 min in 4 ml of DMEM/1% FBS to allow released vinblastine to accumulate in the medium. Media was collected and the cells lysed as described above. The entire volume of media and cell lysates were analyzed by scintillation analysis in a Beckman LS 7800 scintillation counter using Beckman Ready Safe scintillation fluid as a fluor.
  • COS transfectants used for the preparation of RNA were split 1:1 onto fresh 100 cm 2 tissue culture plates immediately following trypsinization one day after transfection.
  • one plate of each sample (approximately lxlO 6 cells) was metabolically labeled and immunoprecipitated with antiserum S32 to assess mature IL-l ⁇ production and secretion as described above.
  • the parallel samples representing the remaining half of the cells replated the previous day, were washed once with PBS before being incubated for 30 min in cysteine- and methionine-deficiem. DMEM/1% dFBS.
  • Oligonucleotide primers for PCR amplification were made to the well-conserved 3" (C-terminal) nucleotide binding site.
  • the 3' primer is GGGCCGTCGAC(G/A)TCIA(G/A)IGCIGAIGTIGC(C/T)TC (G/A)TC.
  • the mdr sequences represented in the primers correspond to 5' (N-terminal) ALVGS-_>G ⁇ GK and 3' (C- terminal) DEATSALD.
  • the amplification reaction was carried out in a Perkin Elmer Cetus Thermal Cycler under the following conditions: five cycles of 94 °C for 30 sec, 45 °C for "60 sec with a 10 sec extension per cycle, 72 °C for 60 sec; then, 35 cycles of 94 °C for 30 sec, 48 °C for 30 sec, 72 °C for 60 sec- The incubations were terminated after a 7 min incubation at 72 °C.
  • the reaction contained 1 ⁇ g of each primer and 1 ng of DNA from an LPS-stimulated human monocyte library in a PBR322 background, See Meyers et al., J. Biol. Chem. (1987) 262:1176-1181; for a lng of DNA from a GM-CSF stimulated monocyte library in a lamdagtll background. See Balcerak et al., 1988. J. Biol . Chem. 263:13937-13941. Only a single band, of approximately 440 bp, was visualized on an agarose gel. The DNA from this band was isolated, digested with EcoRI and Sail, and cloned into the EcoRI and Sail sites of the Bluescript KS+ vector. The resulting clones were sequenced as described above.
  • Test data demonstrates that human mature IL-l ⁇ (the ⁇ form of IL-1 being the predominant IL-1 species produced by human monocytic cells) is released from COS (non-monocytic) kidney cells transfected with RSVILl ⁇ Mature by nonspecific leakage of cytosolic contents and not by a specific secretory mechanism. This release occurs only after long-term (22 h) incubation of the cells following metabolic labeling. Furthermore, human IL-l ⁇ precursor fails to be released into the media even after long-term incubation, apparently due to its short intracellular half-life (3 h) .
  • both LPS-stimulated human monocytes and COS co-transfectants expressing both mature IL-l ⁇ and mdrl were treated with
  • Verapamil is a calcium channel antagonist which also inhibits the transport of various lipophilic, cationic chemotherapeutic drugs from several cell types which exhibit the multiple drug resistance phenotype (Ford et al, Pharm. Reviews f Vol.42, No. 3 (1990)). Results indicate inhibition of IL-l ⁇ secretion by verapamil, although some variability in dose response was observed, thereby giving positive affirmation that the "pump" mechanisms are inhibited and involved in IL-1 secretion. Additional examples clearly indicate, as noted above, that in the absence of mdr, precursor and mature IL-l ⁇ are not secreted. In the presence of mdrl, mature IL-l ⁇ is secreted and pre-cursor IL-l ⁇ is not.
  • verapamil and other calcium channel antagonists bind P-glycoprotein transporters and interfere with their ability to export chemotherapeutic drugs from certain cells, it is clear that these agents do not inhibit drug export in all cases (Ford et al., Pharm. Reviews f Vol.42, No. 3 (1990).

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Abstract

Nouveau mécanisme de régulation de l'activité anti-inflammatoire chez un mammifère, y compris chez l'homme. L'inhibition du transport d'interleukine-1 (IL-1) régulé par la P-glycoprotéine à partir de cellules, par un inhibiteur de la mdr P-glycoprotéine, permet le traitement d'indications dans lesquelles une activité extracellulaire excessive d'IL-1 est en cause. Cette activité a été associée à des maladies telles que l'arthrite rhumatoïde et l'ostéoarthrite.
PCT/US1992/002214 1991-03-19 1992-03-19 Inhibiteurs d'il-1 WO1992016226A1 (fr)

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EP0607774A2 (fr) * 1993-01-08 1994-07-27 Hoechst Aktiengesellschaft Utilisation de leflunomid pour inhiber l'interleukin 1 alpha
EP0607775A3 (fr) * 1993-01-08 1994-08-31 Hoechst Ag
US5663198A (en) * 1993-07-15 1997-09-02 Hoechst Aktiengesellschaft Drug formulations comprising coated, very sparingly water-soluble drugs for inhalational pharmaceutical forms, and process for their preparation
WO1997046254A2 (fr) * 1996-06-05 1997-12-11 Eugene Mechetner Reactifs et procedes d'inhibition de la liberation de cytokines par des cellules sanguines
US5741791A (en) * 1995-12-15 1998-04-21 Novo Nordisk A/S Method of reducing blood glucose
EP0931544A2 (fr) * 1997-12-22 1999-07-28 Kaken Shoyaku Co., Ltd. Inhibiteur de l'activité NF-kB
US6054487A (en) * 1997-03-18 2000-04-25 Basf Aktiengesellschaft Methods and compositions for modulating responsiveness to corticosteroids
US6083706A (en) * 1997-02-26 2000-07-04 Ciblex Corporation Inhibitors of leaderless protein export
WO2001009138A2 (fr) * 1999-07-28 2001-02-08 Millennium Pharmaceuticals, Inc. Antagonistes du recepteur de chimiokine et procedes d'utilisation associes
US6221861B1 (en) * 1998-07-10 2001-04-24 The Regents Of The University Of California Reducing pyrophosphate deposition with calcium antagonists
US6306613B1 (en) 1997-02-26 2001-10-23 Ciblex Corporation Modulators of leaderless protein export and methods for identifying and using the same
JP2002501072A (ja) * 1998-01-21 2002-01-15 ミレニアム・ファーマシューティカルズ・インコーポレイテッド ケモカイン受容体アンタゴニストおよびその使用方法
US6433165B1 (en) 1998-01-21 2002-08-13 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
WO2002096431A1 (fr) * 2001-05-25 2002-12-05 The Regents Of The University Of California Composes optiquement actifs supprimant des proteines malformees
EP1448205A2 (fr) * 2001-10-05 2004-08-25 Combinatorx, Incorporated Combinaisons permettant le traitement des troubles inflammatoires
WO2005013947A2 (fr) * 2003-07-29 2005-02-17 Universitätsklinikum Münster Moyens et procedes de traitement d'une maladie liee a un exces de transport de l'hyaluronane a travers la bicouche lipidique
EP1534256A2 (fr) * 2002-06-17 2005-06-01 Philadelphia Health and Education Corporation Immunomodulation et action sur des processus cellulaires relatifs aux recepteurs de la famille de la serotonine et la barriere hemato-encephalique
EP1551460A1 (fr) * 2002-08-09 2005-07-13 Helen G. Durkin Procede permettant de controler l'efficacite de la tetracycline dans le traitement de l'asthme
US7271176B2 (en) 1998-09-04 2007-09-18 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use thereof
US7419961B2 (en) 2002-10-29 2008-09-02 Zambon S.P.A. 9a-azalides with anti-inflammatory activity
US7488811B2 (en) 2002-08-01 2009-02-10 Zambon Group S.P.A. Macrolide compounds endowed with antiinflammatory activity
US7541365B2 (en) 2001-11-21 2009-06-02 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
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US8080553B2 (en) 2003-10-15 2011-12-20 Zalicus Inc. Methods and reagents for the treatment of immunoinflammatory disorders

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EP0607774A3 (fr) * 1993-01-08 1994-08-31 Hoechst Ag
EP0607775A3 (fr) * 1993-01-08 1994-08-31 Hoechst Ag
US5554637A (en) * 1993-01-08 1996-09-10 Hoechst Aktiengesellschaft Use of leflunomide for inhibiting interleukin 1 alpha
US5556870A (en) * 1993-01-08 1996-09-17 Hoechst Aktiengesellschaft Use of leflunomide for inhibiting interleukin 1 beta
EP0607774A2 (fr) * 1993-01-08 1994-07-27 Hoechst Aktiengesellschaft Utilisation de leflunomid pour inhiber l'interleukin 1 alpha
US5663198A (en) * 1993-07-15 1997-09-02 Hoechst Aktiengesellschaft Drug formulations comprising coated, very sparingly water-soluble drugs for inhalational pharmaceutical forms, and process for their preparation
US5741791A (en) * 1995-12-15 1998-04-21 Novo Nordisk A/S Method of reducing blood glucose
WO1997046254A2 (fr) * 1996-06-05 1997-12-11 Eugene Mechetner Reactifs et procedes d'inhibition de la liberation de cytokines par des cellules sanguines
WO1997046254A3 (fr) * 1996-06-05 1998-02-19 Eugene Mechetner Reactifs et procedes d'inhibition de la liberation de cytokines par des cellules sanguines
US6083706A (en) * 1997-02-26 2000-07-04 Ciblex Corporation Inhibitors of leaderless protein export
US6306613B1 (en) 1997-02-26 2001-10-23 Ciblex Corporation Modulators of leaderless protein export and methods for identifying and using the same
US6054487A (en) * 1997-03-18 2000-04-25 Basf Aktiengesellschaft Methods and compositions for modulating responsiveness to corticosteroids
EP0931544A2 (fr) * 1997-12-22 1999-07-28 Kaken Shoyaku Co., Ltd. Inhibiteur de l'activité NF-kB
EP0931544A3 (fr) * 1997-12-22 2004-08-25 Kaken Shoyaku Co., Ltd. Inhibiteur de l'activité NF-kB
JP2002501072A (ja) * 1998-01-21 2002-01-15 ミレニアム・ファーマシューティカルズ・インコーポレイテッド ケモカイン受容体アンタゴニストおよびその使用方法
JP4853934B2 (ja) * 1998-01-21 2012-01-11 ミレニアム ファーマシューティカルズ， インコーポレイテッド ケモカイン受容体アンタゴニストおよびその使用方法
US6433165B1 (en) 1998-01-21 2002-08-13 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6509346B2 (en) 1998-01-21 2003-01-21 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6613905B1 (en) 1998-01-21 2003-09-02 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6221861B1 (en) * 1998-07-10 2001-04-24 The Regents Of The University Of California Reducing pyrophosphate deposition with calcium antagonists
US7271176B2 (en) 1998-09-04 2007-09-18 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use thereof
WO2001009138A2 (fr) * 1999-07-28 2001-02-08 Millennium Pharmaceuticals, Inc. Antagonistes du recepteur de chimiokine et procedes d'utilisation associes
WO2001009138A3 (fr) * 1999-07-28 2001-09-13 Millennium Pharm Inc Antagonistes du recepteur de chimiokine et procedes d'utilisation associes
WO2002096431A1 (fr) * 2001-05-25 2002-12-05 The Regents Of The University Of California Composes optiquement actifs supprimant des proteines malformees
EP1448205A4 (fr) * 2001-10-05 2007-01-03 Combinatorx Inc Combinaisons permettant le traitement des troubles inflammatoires
US7253155B2 (en) 2001-10-05 2007-08-07 Combinatorx, Inc. Combinations for the treatment of immunoinflammatory disorders
EP1448205A2 (fr) * 2001-10-05 2004-08-25 Combinatorx, Incorporated Combinaisons permettant le traitement des troubles inflammatoires
US7915265B2 (en) 2001-10-05 2011-03-29 Zalicus Inc. Combinations for the treatment of immunoinflammatory disorders
US8653096B2 (en) 2001-11-21 2014-02-18 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use thereof
US9663537B2 (en) 2001-11-21 2017-05-30 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use
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EP1534256A2 (fr) * 2002-06-17 2005-06-01 Philadelphia Health and Education Corporation Immunomodulation et action sur des processus cellulaires relatifs aux recepteurs de la famille de la serotonine et la barriere hemato-encephalique
EP1534256A4 (fr) * 2002-06-17 2007-06-20 Philadelphia Health & Educatio Immunomodulation et action sur des processus cellulaires relatifs aux recepteurs de la famille de la serotonine et la barriere hemato-encephalique
US7704960B2 (en) 2002-08-01 2010-04-27 Zambon Group S.P.A. Macrolide compounds endowed with antiinflammatory activity
EP2258708A1 (fr) 2002-08-01 2010-12-08 Zambon S.p.A. Composés de macrolides ayant une activité anti-inflammatoire
US7488811B2 (en) 2002-08-01 2009-02-10 Zambon Group S.P.A. Macrolide compounds endowed with antiinflammatory activity
EP1551460A1 (fr) * 2002-08-09 2005-07-13 Helen G. Durkin Procede permettant de controler l'efficacite de la tetracycline dans le traitement de l'asthme
EP1551460A4 (fr) * 2002-08-09 2008-02-13 Helen G Durkin Procede permettant de controler l'efficacite de la tetracycline dans le traitement de l'asthme
US7419961B2 (en) 2002-10-29 2008-09-02 Zambon S.P.A. 9a-azalides with anti-inflammatory activity
US7732459B2 (en) 2002-11-13 2010-06-08 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use therefor
US7977350B2 (en) 2002-11-13 2011-07-12 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use therefor
US8394817B2 (en) 2002-11-13 2013-03-12 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use therefor
US9334283B2 (en) 2002-11-13 2016-05-10 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use thereof
AU2009201460B2 (en) * 2003-07-29 2011-05-12 Universitaetsklinikum Muenster Means and methods for treating a disease which is associated with an excess transport of hyaluronan across a lipid bilayer
AU2004262494B2 (en) * 2003-07-29 2009-01-15 Universitaetsklinikum Muenster Means and methods for treating a disease which is associated with an excess transport of hyaluronan across a lipid bilayer
WO2005013947A3 (fr) * 2003-07-29 2005-04-07 Universitaetsklinikum Muenster Moyens et procedes de traitement d'une maladie liee a un exces de transport de l'hyaluronane a travers la bicouche lipidique
WO2005013947A2 (fr) * 2003-07-29 2005-02-17 Universitätsklinikum Münster Moyens et procedes de traitement d'une maladie liee a un exces de transport de l'hyaluronane a travers la bicouche lipidique
US8080553B2 (en) 2003-10-15 2011-12-20 Zalicus Inc. Methods and reagents for the treatment of immunoinflammatory disorders

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