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WO1996001645A1 - Utilisation de composes peptidiques de muramyle - Google Patents

Utilisation de composes peptidiques de muramyle Download PDF

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Publication number
WO1996001645A1
WO1996001645A1 PCT/GB1995/001619 GB9501619W WO9601645A1 WO 1996001645 A1 WO1996001645 A1 WO 1996001645A1 GB 9501619 W GB9501619 W GB 9501619W WO 9601645 A1 WO9601645 A1 WO 9601645A1
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WO
WIPO (PCT)
Prior art keywords
acetyl
alanyl
glucosaminyl
acetylmuramyl
gmdp
Prior art date
Application number
PCT/GB1995/001619
Other languages
English (en)
Inventor
Philip Ledger
Original Assignee
Peptech(Uk) Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Peptech(Uk) Limited filed Critical Peptech(Uk) Limited
Priority to CZ9747A priority Critical patent/CZ4797A3/cs
Priority to AU28935/95A priority patent/AU2893595A/en
Priority to JP8504191A priority patent/JPH10505580A/ja
Priority to EP95924437A priority patent/EP0768888A1/fr
Priority to SK26-97A priority patent/SK2697A3/sk
Priority to KR1019970700171A priority patent/KR970704465A/ko
Publication of WO1996001645A1 publication Critical patent/WO1996001645A1/fr
Priority to BG101126A priority patent/BG101126A/xx

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Classifications

    • 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
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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

Definitions

  • the present invention relates to the treatment of inflammatory dermatological conditions and in particular to the treatment of psoriasis.
  • Psoriasis is a non-infective, usually chronic inflammatory skin disease occurring in about 2% of the population. It has a number of clinical manifestations, the most common of which is raised, red, roughened plaques covered by silvery scales. The nails are involved in about 50% of cases, and arthritic involvement may occur. The external changes in the skin are associated with histological changes in the disposition of the epidermis, and vascularisation of sub-epidermal tissues. Infiltration of lymphocytes commonly occurs. The occurrence of psoriasis results from a combination of environmental and genetic factors. Numerous studies have demonstrated a range of changes in functionality of the epidermis and immune system of psoriatics, but no comprehensive theory yet exists which can accounts for all the observed abnormalities.
  • prototype muramyl dipeptide (now frequently referred to as "prototype muramyl dipeptide” or “prototype MDP”) to protect mice against bacterial infection ( Klebsiella pneumonia) has been described (Chedid e ⁇ al , Proc . Na t ' l . Acad . Sci . USA, 74 2089 (1977) ) .
  • analogues of prototype muramyl dipeptide were synthesised, some of which have been proposed as treatments for the restoration of immune function or the non-specific stimulation of the immune system.
  • These analogues, and prototype MDP itself, are muramyl peptide compounds.
  • MTP-PE was found to be particularly useful as an adjuvant with a Herpes simplex virus subunit vaccine.
  • Muramyl peptides have also been proposed for use as anti viral agents (Ikeda et al , Antiviral Res 5:207-15 (1985)) and in the treatment of cancers (Phillips NC and Tsao, M- S, Cancer Immunol Immunother. 33:85-90 (1991)) .
  • US-A-4357322 discloses the use of various muramyl and desmethylmuramyl dipeptides in treating inflammation. No mention, however, is made of GMDP or psoriasis.
  • a muramyl peptide compound in the preparation of an agent for the treatment or prophylaxis of an inflammatory dermatological condition.
  • R 1 represents a hydrogen atom or a C 1 -C 22 acyl group
  • R 2 represents a hydrogen atom or a C ⁇ -C 22 acyl group
  • R 3 represents a hydrogen atom or a C,-C 6 alkyl group
  • R 4 represents a C ⁇ -C 21 alkyl group or a C 5 or C 10 aryl group
  • R 5 represents a hydrogen atom
  • R represents the residue of an amino acid or a linear peptide built up of from 2 to 6 amino acid residues, at least one of the residues being optionally substituted with a lipophilic group;
  • Preferred acyl groups for R 1 and R 2 are C ⁇ Cg acyl groups such as acetyl; it will be appreciated that the carbon count in the acyl group does not include the carbonyl moiety.
  • Preferred alkyl groups for R 3 are C ⁇ , alkyl groups such as methyl and ethyl.
  • R preferably represents a mono-, di- or tri-peptide.
  • the proximal peptide residue (or the only peptide residue, if there is only one) is preferably that of an L-amino acid. Examples include:
  • L-alanyl is preferred, as is L-threonyl.
  • the next amino acid from the proximal end of the peptide is preferably of the D-configuration. It is preferably acidic and may be D-glutamic or D-aspartic acid or a mono-, di- or mixed alkyl ester, amide or C 1 -C 4 alkyl amide thereof. (The expression “mixed” is illustrated when one carboxyl group is amidated and the other esterified. D-isoglutamine and D- glutamate are preferred.
  • a third amino acid residue from the proximal end of the chain is preferably of the L- configuration, as indicated above in relation to the proximal amino acid residue.
  • L-alanyl and L-lysyl are preferred.
  • the amino acid residue or linear peptide is optionally substituted with at least one lipophilic group.
  • the lipophilic group may be a C 10 -C 22 acyl group such as stearoyl or a di- (C 10 -C 22 acyl) -s ⁇ -glycero-3' -hydroxy- phospheryloxy-group wherein for example each of the C 1Q -C 22 acyl groups can be a palmitoyl group.
  • the lipophilic group may alternatively (or in addition, as more than one substitution may be present) be a C ⁇ C ⁇ , ester group, such as a C 2 -C 6 ester group: a butyl ester is an example.
  • muramyl dipeptides within the scope of general formula I include: muroctasin, otherwise known as MDP-Lys (L18) (N 2 - (N- acetylmuramyl-L-alanyl-D-isoglutaminyl) -N 6 -stearoyl- L-lysine) ;
  • MTP-PE N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L- alanyl-2- (1' ,2' -dipalmitoyl-sn-glycero-3' -hydroxy- phosphoryloxy) ethylamide, monosodium
  • t-MDP N-acetylmuramyl-L-threonyl-D-isoglutamine
  • R represents a residue of an amino acid or a linear peptide built of from 2 to 6 amino acid residues, at least one of the residues being optionally substituted with a lipophilic group;
  • n 1 or 2.
  • R Preferred values for R are as described above in relation to general formula I. It is particularly preferred that the peptide R correspond to the peptide in prototype MDP (L-Ala-D-isoGln) . Alternatively, in another preferred embodiment, R may represent L-Ala-D-Glu.
  • n 1
  • GMDP N-acetyl-D-glucosaminyl- ( ⁇ l-4 ) -N-acetylmuramyl-L-alanyl- D-isoglutamine
  • This compound (Compound II in US-A-4395399) , also known as glycopin, has already undergone preclinical toxicity testing and pharmacokinetic investigations required for licensing for clinical use in the USSR (as it then was) .
  • the acute toxicity in mice, measured by the LD S0 test is 7 g/kg. This figure shows the compound to be almost an order of magnitude less toxic than muroctasin which has an LD 50 value in mice of 625 g/kg.
  • GMDP-A N-acetyl-D-glucosaminyl- (01-4) -N- acetylmuramyl-L-alanyl-D-glutamic acid
  • GMDP-LL N-acetyl-D-glucosaminyl- (31-4) -N acetylmuramyl-L-alanyl- L-isoglutamine
  • GMDP-OBu N-acetyl-D-glucosaminyl- (jSl-4) -N acetylmuramyl-L-alanyl- D-glutamine n-butyl ester
  • GMDP-Lys N-acetyl-D-glucosaminyl- (/31-4) -N acetylmuramyl-L-alanyl- D-isoglutaminyl-L-lysine (GMDP-Lys) which has the structure:
  • N-Acetyl-D-glucosaminyl- (01--4) -N-acetylmuramyl-L-alanyl- D-glutamic acid dibenzyl ester which has the structure:
  • N-Acetyl-D-glucosaminyl- (01--4) -N-acetylmuramyl-N-methyl- L-alanyl-D-isoglutamine which has the structure:
  • GMDPA N-Acetyl-D-glucosaminyl- (01--4) -N-acetylmuramyl- (01--4) - N-acetyl-D-glucosaminyl- (01--4) -N-acetylmuramyl-bis- (L- alanyl-D-isoglutaminyl-L-lysine) which has the structure:
  • N-Acetyl-D-glucosaminyl- (01--4) -N-acetylmuramyl-L-alanyl - D-isoglutaminyl-L-glutamyl-L-tryptophan which has the structure:
  • N-Acetyl-D-glucosaminyl- (01--4) -N- ace tylmuramyl- L-alanyl - D-isoglutaminyl- e -aminohexanoyl-L-glutamyl-L-tryptophan which has the structure:
  • N-acetylmuramyl-L-threonyl-D-isoglutamine which has the structure:
  • N-acetylmuramyl -L-alanyl -D-glutamine n-butyl ester which has the structure :
  • the most preferred compound is GMDP followed by GMDP-A, and murabutide.
  • Glucosaminyl-muramyl dipeptides within the scope of general formula II can be prepared relatively cheaply and in reasonably large quantities by the process disclosed in US-A-4395399.
  • the preparation disclosed is based on the extraction and purification of the disaccharide component from the bacterium Micrococcus lysodecticus and its subsequent chemical linkage to a dipeptide synthesised for example by conventional peptide chemistry.
  • the disaccharide may equally well be chemically synthesised using standard sugar chemistry.
  • Inflammatory dermatological conditions treatable, or preventable, by means of the invention include all types of psoriasis, including discoid or plaque psoriasis, flexural psoriasis, scalp psoriasis, palmar/plantar psoriasis, guttate psoriasis, erythrodermic psoriasis and pustular psoriasis, psoriatic arthritis and changes in the nails resulting from psoriasis.
  • psoriasis including discoid or plaque psoriasis, flexural psoriasis, scalp psoriasis, palmar/plantar psoriasis, guttate psoriasis, erythrodermic psoriasis and pustular psoriasis, psoriatic arthritis and changes in the nails resulting from psoriasis.
  • GMDP psoriasis area and severity index
  • muramyl peptide compounds should have this beneficial effect as muramyl peptides are generally considered to be pro-inflammatory immunostimulants, whereas regression of inflamed lesions would generally be considered as requiring anti- inflammatory treatment.
  • the muramyl peptide compound GMDP was applied to the skin of mice in solution in ethanol. At control sites, ethanol alone was applied. Some groups of animals received irradiation with ultra violet light (UVB) or received an application of cis urocanic acid (cUCA) , both treatments known to provoke changes in the cutaneous immune system.
  • UVB ultra violet light
  • cUCA cis urocanic acid
  • GMDP treatment caused a loss of ATPase staining and retraction of dendritic processes of the epidermal dendritic cells, which is generally associated with a loss of immunological function. i.e., the GMDP reduced the potential immunoreactivity of the skin.
  • UVB phototherapy alone is a treatment for psoriasis, thereby supporting the efficacy of muramyl peptide compounds in the invention.
  • GMDP does not cause migration of dendritic cells from the epidermis to draining lymph nodes.
  • GMDP is having a fundamental effect on dendritic Langerhans cells, which are the primary immune component of the epidermis. Since there is evidence to support a role for Langerhans cells in the pathogenesis of psoriasis (Placek et al , Acta Derm Venereol (Stockh) 68:369-77 (1988)), it is possible that a down-regulation of the activity of these cells is able to reduce the severity of the disease.
  • the experiments with the mice were performed by topical application of GMDP, but GMDP is known to be orally bioavailable, and so GMDP orally administered, as in the clinical trial, could be expected to exert an effect in the skin.
  • muramyl peptides will have utility in the treatment of a range of immunologically based inflammatory skin diseases for which it has never previously been proposed.
  • the mucous membranes lining the buccal cavity, the vagina and the uterine cervix also contain Langerhans cells, these too are target organs for muramyl peptide treatment.
  • muramyl peptide compound in the preparation of an agent for the treatment or prophylaxis of immune-related diseases cf the skin and mucous membranes.
  • eczema otherwise known as atopic eczema or atopic dermatitis
  • seborrhoeic eczema pompholyx
  • contact dermatitis urticaria
  • erythroderma erythroderma
  • lichen planus atopic dermatitis
  • vitiligo alopoecia areata.
  • Muramyl peptide compounds in the invention has been demonstrated using oral administration.
  • the formulation in this instance consisted of tablets containing pharmaceutically acceptable excipients, namely lactose, starch, polyvidone, magnesium stearate and talc.
  • Muramyl peptide compounds may be formulated for sustained and/or delayed delivery if desired. Gastric coating is another option.
  • a daily oral dosage in the range of from 0.1 to 100 mg per day (or per unit dose) may be found acceptable, with a range of 0.5 to 50 mg being preferred. Within this preferred range, an optimal daily dosage would be within the range 2 to 30 mg or indeed 2 to 20 mg.
  • duration of administration may be varied. The duration will of course depend, to some extent, on dosage level, i.e. lower dose results in longer required duration of dosage. In general terms, the duration of dosage will be in the range of 1-60 days, preferably 1-30 days and most preferably 1-14 days. It has been demonstrated that muramyl peptide compounds do have an affect on the cutaneous immune system after topical administration.
  • a topical formulation of muramyl peptide compound(s) will be preferred, when for example functioning of the gastrointestinal tract of a patient is compromised by disease or surgery, or in the case of particularly recalcitrant skin diseases where a particularly high local concentration of muramyl peptide compound is desired.
  • a topical formulation of a muramyl peptide compound According to a third aspect of the invention, there is provided a topical formulation of a muramyl peptide compound.
  • the formulation which may be presented as an ointment, lotion or cream, may contain pharmaceutically acceptable excipients or carriers, with due regard being taken of the ability of the formulation effectively to release the muramyl peptide into the skin.
  • the formulation may even enhance the passage of said muramyl compounds by the incorporation of so called permeation enhancers.
  • Muramyl peptide compounds may be used either singly or in combination with each other in the invention. Also, muramyl peptide compounds may be used in combination with other compounds, whether formulated together or separately; for example, a muramyl peptide compound may be administered orally and another compound administered topically. When used in combination, either with each other or with other compounds, administration can be simultaneous, separate or sequential.
  • the present invention provides a method for the prophylaxis or treatment of an inflammatory dermatological condition, comprising administering to a patient a muramyl peptide compound.
  • FIGURE 1 is a plot showing changes in psoriasis severity and area index (PASI) during the course of treatment with GMDP or placebo.
  • PASI psoriasis severity and area index
  • GMDP was dissolved in ethanol at 1 mg/ml and 0.1 mg/ml. Twenty microlitres of this solution, or vehicle (ethanol) control was painted on to the dorsal sides of the ears of mice which had previously been "stripped" with adhesive tape to remove the superficial barrier layers. Other mice were irradiated with a dose of UVB (144 mJ/cm 2 ) known to influence Langerhans cell (LC) ATPase expression.
  • UVB 144 mJ/cm 2
  • LC Langerhans cell
  • the positive control was cis-urocanic acid (cUCA) , a substance generated in the epidermis under the influence of UVB, and believed to be implicated in the mediation of UVB-induced changes in LC function.
  • cUCA cis-urocanic acid
  • mice Twenty four hours later mice were killed, epidermis was removed from the dorsal surface of the ears, and stained to reveal ATPase activity. Cells showing staining were counted and expressed as cells/mm 2 . The morphology of the cells was also noted.
  • Results are summarised in Tables 2 and 3.
  • GMDP at the two doses studied significantly reduced the number of ATPase positive cells as compared to vehicle controls.
  • the positive control treatments (UVB irradiation and c- UCA) also reduced cells, as expected.
  • mice were treated with ethanol, GMDP at 1 mg/ml in ethanol, or UVB at 96 mJ/cm.2. Forty eight hours later mice were killed, the auricular ("draining") lymph nodes excised, and dendritic cells purified and counted.
  • UVB significantly enhanced the number of dendritic cells in lymph nodes.
  • GMDP showed no significant effect.

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Abstract

Des composés peptidiques de muramyle, notamment N-acétyl-D-glucosaminyl-(β 1-4)-N-acétylmuramyl-L-alanyl-D-isoglutamine (GMDP), sont utilisés dans le traitement ou la prophylaxie d'états dermatologiques inflammatoires, tels que le psoriasis, et dans le traitement ou la prophylaxie de maladies immunes de la peau et des muqueuses.
PCT/GB1995/001619 1994-07-11 1995-07-10 Utilisation de composes peptidiques de muramyle WO1996001645A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CZ9747A CZ4797A3 (en) 1994-07-11 1995-07-10 Use of muramylpeptide compounds and pharmaceutical composition
AU28935/95A AU2893595A (en) 1994-07-11 1995-07-10 Use of muramyl peptide compounds
JP8504191A JPH10505580A (ja) 1994-07-11 1995-07-10 ムラミルペプチド化合物の使用
EP95924437A EP0768888A1 (fr) 1994-07-11 1995-07-10 Utilisation de composes peptidiques de muramyle
SK26-97A SK2697A3 (en) 1994-07-11 1995-07-10 Use of muramyl peptide compounds and pharmaceutical composition
KR1019970700171A KR970704465A (ko) 1994-07-11 1995-07-10 무라밀 펩티드 화합물의 용도(use of muramyl peptide compounds)
BG101126A BG101126A (en) 1994-07-11 1997-01-10 The use of muramylpeptide compounds

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9413935A GB9413935D0 (en) 1994-07-11 1994-07-11 Use of maramyl peptide compounds
GB9413935.9 1994-07-11
CN95194573A CN1155245A (zh) 1994-07-11 1995-07-10 胞壁酰肽化合物的应用

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WO1996001645A1 true WO1996001645A1 (fr) 1996-01-25

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EP (1) EP0768888A1 (fr)
JP (1) JPH10505580A (fr)
CN (1) CN1155245A (fr)
AU (1) AU2893595A (fr)
BG (1) BG101126A (fr)
CA (1) CA2194678A1 (fr)
CZ (1) CZ4797A3 (fr)
GB (1) GB9413935D0 (fr)
HU (1) HUT77290A (fr)
IL (1) IL114542A0 (fr)
SK (1) SK2697A3 (fr)
WO (1) WO1996001645A1 (fr)
ZA (1) ZA955763B (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998046251A1 (fr) * 1997-04-11 1998-10-22 Oleg Vitalievich Kaljuzhin Regulateur immunologique, composition pharmaceutique possedant une activite antitumorale et additif alimentaire
WO1998052556A1 (fr) * 1997-05-20 1998-11-26 Scotia Holdings Plc Compositions de glucosamine et d'acide gras et leur utilisation
WO1999062537A1 (fr) * 1998-06-04 1999-12-09 The Rockefeller University Procedes et agents permettant la modulation de la reponse immunitaire et de l'inflammation par modulation des proteines membranaires des monocytes et des cellules dendritiques
WO2008048076A1 (fr) 2006-10-20 2008-04-24 Amorepacific Corporation Composition pour le traitement de la dermatite atopique comprenant de la glucosamine et des dérivés de cette dernière et procédé de traitement de la dermatite atopique faisant intervenir de la glucosamine et des dérivés de cette dernière
WO2008070564A1 (fr) * 2006-12-01 2008-06-12 The Government Of The U.S.A, As Represented By The Secretary, Departmentof Health And Human Services Utilisations du dipeptide muramyle (mdp) dans le traitement de l'inflammation
FR2933984A1 (fr) * 2008-07-15 2010-01-22 Univ Bourgogne D,d muramyldipeptide,composes derives et utilisation pour le traitement des plaques atheromateuses
EP2196202A1 (fr) * 2001-02-14 2010-06-16 Thomas Luger Lys-Pro-Thr et Lys-Pro pour l'inhibition des inflammations
WO2017098529A1 (fr) 2015-12-10 2017-06-15 Bharat Biotech International Limited Nouveau composé dérivé de muramyle, synthèse et utilisations associées
WO2017103944A1 (fr) 2015-12-15 2017-06-22 Bharat Biotech International Limited Nouveau composé dérivé des peptides de muramyle, sa synthèse et ses utilisations
EP1842527B1 (fr) * 2006-04-07 2019-06-26 L'Oréal Utilisation de composé c-glycoside comme agent activateur et régulateur de l'immunité cutanée
US10610564B2 (en) 2015-02-26 2020-04-07 Stc.Unm IRGM and precision autophagy controls for antimicrobial and inflammatory disease states and methods of detection of autophagy
US11859021B2 (en) 2021-03-19 2024-01-02 Icahn School Of Medicine At Mount Sinai Compounds for regulating trained immunity, and their methods of use

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DE3129759A1 (de) * 1980-07-29 1982-06-03 Syntex (U.S.A.) Inc., 94304 Palo Alto, Calif. Muramylpeptide enthaltende arzneimittel und ihre verwendung
US4698330A (en) * 1983-06-27 1987-10-06 President & Fellows Of Harvard College Somnogenic compositions and method of use
EP0406175A2 (fr) * 1989-06-29 1991-01-02 Sandoz Ltd. Dérivés du muramyldipeptide
WO1993010148A1 (fr) * 1991-11-19 1993-05-27 Peptech (Uk) Limited Composes de muramyl utilises dans le traitement de choc septique
WO1993016713A2 (fr) * 1992-02-28 1993-09-02 Peptech (Uk) Limited Composes a usage medical
WO1995010293A1 (fr) * 1993-10-08 1995-04-20 Peptech (Uk) Limited Composes a usage medicinal
WO1995018146A1 (fr) * 1993-12-29 1995-07-06 Sandoz Ltd. Glycerol substitue

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DE3129759A1 (de) * 1980-07-29 1982-06-03 Syntex (U.S.A.) Inc., 94304 Palo Alto, Calif. Muramylpeptide enthaltende arzneimittel und ihre verwendung
US4698330A (en) * 1983-06-27 1987-10-06 President & Fellows Of Harvard College Somnogenic compositions and method of use
EP0406175A2 (fr) * 1989-06-29 1991-01-02 Sandoz Ltd. Dérivés du muramyldipeptide
WO1993010148A1 (fr) * 1991-11-19 1993-05-27 Peptech (Uk) Limited Composes de muramyl utilises dans le traitement de choc septique
WO1993016713A2 (fr) * 1992-02-28 1993-09-02 Peptech (Uk) Limited Composes a usage medical
WO1995010293A1 (fr) * 1993-10-08 1995-04-20 Peptech (Uk) Limited Composes a usage medicinal
WO1995018146A1 (fr) * 1993-12-29 1995-07-06 Sandoz Ltd. Glycerol substitue

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Title
KOJIMA H. ET AL: "General pharmacological properties of muroctasin", ARZNEIMITTEL FORSCHUNG DRUG RESEARCH, vol. 38, no. 7A, AULENDORF, pages 1002 - 1009 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998046251A1 (fr) * 1997-04-11 1998-10-22 Oleg Vitalievich Kaljuzhin Regulateur immunologique, composition pharmaceutique possedant une activite antitumorale et additif alimentaire
WO1998052556A1 (fr) * 1997-05-20 1998-11-26 Scotia Holdings Plc Compositions de glucosamine et d'acide gras et leur utilisation
WO1999062537A1 (fr) * 1998-06-04 1999-12-09 The Rockefeller University Procedes et agents permettant la modulation de la reponse immunitaire et de l'inflammation par modulation des proteines membranaires des monocytes et des cellules dendritiques
EP2196202A1 (fr) * 2001-02-14 2010-06-16 Thomas Luger Lys-Pro-Thr et Lys-Pro pour l'inhibition des inflammations
EP1842527B1 (fr) * 2006-04-07 2019-06-26 L'Oréal Utilisation de composé c-glycoside comme agent activateur et régulateur de l'immunité cutanée
WO2008048076A1 (fr) 2006-10-20 2008-04-24 Amorepacific Corporation Composition pour le traitement de la dermatite atopique comprenant de la glucosamine et des dérivés de cette dernière et procédé de traitement de la dermatite atopique faisant intervenir de la glucosamine et des dérivés de cette dernière
WO2008070564A1 (fr) * 2006-12-01 2008-06-12 The Government Of The U.S.A, As Represented By The Secretary, Departmentof Health And Human Services Utilisations du dipeptide muramyle (mdp) dans le traitement de l'inflammation
FR2933984A1 (fr) * 2008-07-15 2010-01-22 Univ Bourgogne D,d muramyldipeptide,composes derives et utilisation pour le traitement des plaques atheromateuses
US10610564B2 (en) 2015-02-26 2020-04-07 Stc.Unm IRGM and precision autophagy controls for antimicrobial and inflammatory disease states and methods of detection of autophagy
WO2017098529A1 (fr) 2015-12-10 2017-06-15 Bharat Biotech International Limited Nouveau composé dérivé de muramyle, synthèse et utilisations associées
WO2017103944A1 (fr) 2015-12-15 2017-06-22 Bharat Biotech International Limited Nouveau composé dérivé des peptides de muramyle, sa synthèse et ses utilisations
US10576147B2 (en) * 2015-12-15 2020-03-03 Bharat Biotech International Limited Muramyl peptide derivative compound, synthesis and uses thereof
US11859021B2 (en) 2021-03-19 2024-01-02 Icahn School Of Medicine At Mount Sinai Compounds for regulating trained immunity, and their methods of use

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BG101126A (en) 1997-09-30
HU9700071D0 (en) 1997-02-28
JPH10505580A (ja) 1998-06-02
CN1155245A (zh) 1997-07-23
ZA955763B (en) 1997-01-13
AU2893595A (en) 1996-02-09
GB9413935D0 (en) 1994-08-31
CZ4797A3 (en) 1997-07-16
CA2194678A1 (fr) 1996-01-25
SK2697A3 (en) 1997-08-06
IL114542A0 (en) 1995-11-27
EP0768888A1 (fr) 1997-04-23
HUT77290A (hu) 1998-03-30

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