EP1208101A1 - Antagonistes du recepteur de la vitronectine utiles pour le traitement des accidents vasculaires cerebraux - Google Patents

Antagonistes du recepteur de la vitronectine utiles pour le traitement des accidents vasculaires cerebraux

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Publication number
EP1208101A1
EP1208101A1 EP00952558A EP00952558A EP1208101A1 EP 1208101 A1 EP1208101 A1 EP 1208101A1 EP 00952558 A EP00952558 A EP 00952558A EP 00952558 A EP00952558 A EP 00952558A EP 1208101 A1 EP1208101 A1 EP 1208101A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
crg
het
vitronectin receptor
nrg
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00952558A
Other languages
German (de)
English (en)
Other versions
EP1208101A4 (fr
Inventor
Frank C. Barone
Tian-Li Yue
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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 SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP1208101A1 publication Critical patent/EP1208101A1/fr
Publication of EP1208101A4 publication Critical patent/EP1208101A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • This invention relates to the use of antagonists of the vitronectin receptor to 5 treat stroke.
  • Integrins are a superfamily of cell adhesion receptors that couple intracellular cytoskeletal elements with extracellular matrix molecules. These cell surface
  • 10 adhesion receptors include oCy ⁇ (the vitronectin receptor).
  • the vitronectin receptor ⁇ v B 3 is expressed on a number of cells, including endothelial, smooth muscle, osteoclast, and tumor cells, and, thus, it has a variety of functions.
  • the ⁇ v B 3 receptor expressed on the membrane of osteoclast cells mediates the adhesion of osteoclasts to the bone matrix, a key step in the bone resorption process. Ross, et al., J. Biol.
  • v ⁇ 3 receptor expressed on human aortic smooth muscle cells mediates their migration into neointima, a process which can lead to restenosis after percutaneous coronary angioplasty. Brown, et al., Cardiovascular Res., 1994, 28, 1815. Additionally, Okada, et al., Am. J. Pathol, 1996, 149(1), 37 suggest that oc v 6 3 plays a role in vascular integrity and remodeling following focal
  • vitronectin receptor antagonists would be useful in treating stroke and the post-traumatic injury associated with stroke.
  • the present invention provides a new method of treatment of stroke in a mammal, in particular a man, which comprises administering to a subject in need thereof an effective amount of a vitronectin receptor antagonist.
  • the present invention is a therapeutic method for treating stroke and a method for protecting the central nervous system from traumatic and post-traumatic injury associated with stroke, e.g., prevention of neurotrauma, and the reduction of morbidity resulting from the sequelae of stroke.
  • the method utilizes a class of
  • vitronectin receptor antagonists include, but are not limited to, the following: Benzazepine ethers of the formula (I), which are described in PCT Application No. PCT/US97/18001, filed October 1, 1997, published as WO 98/14192 on April 9, 1998:
  • R 1 is R 7 , or A-Co- 4 alkyl, A-C 2 - 4 alkenyl, A-C 2 - 4 alkynyl, A-C3- 4 ⁇ xoalkenyl, A-C 3 - 4 ⁇ xoalkynyl, A-C ⁇ _4aminoalkyl, A-C3_4aminoalkenyl, A-C ⁇ aminoalkynyl, optionally substituted by any accessible combination of one or more of R 10 or R 7 ;
  • A is H, C3.6cycloalkyl, Het or Ar;
  • R 7 is -COR 8 , -COCR' 2 R 9 , -C(S)R 8 , -S(O) m OR', -S(O) m NR'R", -PO(OR'), -PO(OR') 2 , -NO 2 , or tetrazolyl; each R 8 independently is -OR', -NRR", -NR'SO 2 R', -NROR', or
  • R9 is -OR', -CN, -S(O) r R ⁇ -S(O) m NR' 2 , -C(O)R', C(O)NR' 2 , or -CO 2 R';
  • R l O is H, halo, -OR 11 , -CN, -NR'R 11 , -NO 2 , -CF 3 , CF 3 S(O) , -CO 2 R', -CONR' 2 , A-C 0 -6alkyl-, A-C ⁇ 6 oxoalkyl-, A-C 2 . 6 alkenyl-, A-C 2 . 6 alkynyl-, A-Co-6alkyloxy-, A-Co-6alkylamino- or A-Co- 6 alkyl-S(O) r -;
  • R 11 is R', -C(O)R', -C(O)NR' 2) -C(O)OR ⁇ -S(O) m R', or -S(O) m NR' 2 ;
  • W is -(CHRg)a-U- (CHRg)b-;
  • G is NR e , S or O;
  • Rg is H, C ⁇ alkyl, Het-C 0 . 6 alkyl, C3-7cycloalkyl-C 0 . 6 alkyl or Ar-Co_ 6 alkyl;
  • R k is Rg, -C(O)Rg, or -C(O)OR f ;
  • R 1 is is H, Cj. 6 alkyl, Het-C 0 . 6 alkyl, C3-7cycloalkyl-C 0 _ 6 alkyl, Ar- C 0 . 6 alkyl, or C ⁇ alkyl substituted by one to three groups chosen from halogen, CN, NRg 2 , ORg, SRg, CO 2 Rg, and CON(Rg) 2 ;
  • R f is H, C j ⁇ alkyl or Ar-C 0 . 6 alkyl
  • R e is H, Ar-C 0 . 6 alkyl, Het-C 0 . 6 alkyl, C3-7cycloalkyl-C 0 . 6 alkyl, or (CH 2 ) k CO 2 Rg;
  • R b and R c are independently selected from H, C j . 6 alkyl, Ar-Co_6alkyl, Het- C 0 . 6 alkyl, or C3_6cycloalkyl-C 0 . 6 alkyl, halogen, CF 3 , OR f , S(O) k R f , COR f , NO 2 , N(R f ) 2 , CO(NR f ) 2 , CH 2 N(R f ) , or R b and R c are joined together to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted by up to three substituents chosen from halogen, CF 3 , C ⁇ alkyl, OR f , S(O) k R f , COR f , CO 2 R f , OH, NO 2 , N(R f ) 2) CO(NR f ) 2 , and
  • R' is H, Ci- ⁇ alkyl, Ar-Co-6alkyl or C3-6cycloalkyl-Co- 6 alkyl;
  • R" is R', -C(O)R' or -C(O)OR';
  • R'" is H, C 1 . 6 alkyl, Ar-C 0 . 6 alkyl, Het-C 0 . 6 alkyl, or C3-6cycloalkyl-C 0 .
  • R is H, halo, -OR g , -SR g , -CN, -NR g R k , -NO 2 , -CF 3 , CF 3 S(O) r -, -CO 2 R g , -COR g or -CONR g 2 , or C ⁇ ealkyl optionally substituted by halo, -OR g , -SR g , -CN, -NR g R", -NO 2 , -CF 3 , R'S(O) r -, -CO 2 R g , -COR g or -CONR g 2 ; a is 0, 1 or 2; b is 0, 1 or 2; k is 0, 1 or 2; m is 1 or 2; r is 0, 1 or 2; s is 0, 1 or 2; u is 0 or 1 ; and v is 0 or 1 ; or a pharmaceutically acceptable salt thereof.
  • Preferred formula (I) compounds used in the method of this invention are (S)-3-oxo-8-[3-(pyridin-2-ylamino)-l-propyloxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5- tetrahydro-lH-2-benzazepine-4-acetic acid and (S)-8-[2-[6-(methylamino)pyridin-2- yl]-l-ethoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-lH-2-benzazepine-4- acetic acid, or pharmaceutically acceptable salts thereof.
  • vitronectin receptor antagonists used in the method of this invention include those antagonists described in the following: PCT
  • PCT/US95/08306 filed June 29, 1995, published as WO 96/00730 on January 11, 1996
  • PCT Application No. PCT/US95/08146 filed June 29, 1995, published as WO 96/00574 on January 11, 1996
  • PCT Application No. PCT/US96/11108 filed June 28, 1996, published as WO 97/01540 on January 16, 1997
  • PCT Application No. PCT/US96/20748 filed December 20, 1996, published as WO 97/24119 on July 10, 1997
  • PCT Application No. PCT US96/20744 filed December 20, 1996, published as WO 97/24122 on July 10, 1997
  • PCT/US96/20327 filed December 20, 1996, published as WO 97/24124 on July 10, 1997;
  • PCT Application No. PCT/US98/00490 filed January 8, 1998, published as WO 98/30542 on July 16, 1998;
  • PCT Application No. PCT/US99/28662 filed December 3, 1999, published as WO 00/33838 on June 15, 2000.
  • the preferred compound in PCT Application WO 00/33838 is (S)-10,l l-dihydro-3-[2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)-l- ethoxy]-5H-dibenzo[a,d]cycloheptene-10-acetic acid.
  • This compound is useful in the method of this invention.
  • the above list of vitronectin receptor antagonists for use in the method of the present invention were taken from published patent applications. Reference should be made to each patent application for its full disclosure, including the methods of preparing the disclosed compounds, the entire disclosure of each patent application being incorporated herein by reference. In accordance with the present invention, it has been found that the administration of a vitronectin receptor antagonist to a stroke patient minimizes the worsening of the infarction and aids in the prevention of a second stoke.
  • ischemic organ trauma as in stroke, a high proportion of ischemic organ cells become irreversibly damaged and necrotic, the extent of injury being dependent upon the length of time that the trauma, e.g. the arterial occlusion, persists.
  • the vitronectin receptor antagonist is incorporated into standard pharmaceutical compositions. It can be administered orally, parenterally, rectally, topically or transdermally.
  • compositions of the vitronectin receptor antagonist may be formulated as solutions or lyophilized powders for parenteral administration.
  • Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation may be a buffered, isotonic, aqueous solution.
  • suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • the vitronectin receptor antagonist may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration.
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • Liquid carriers include syrup, peanut oil, olive oil, saline and water.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
  • Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
  • the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • the compound is administered either orally or parenterally to the patient, in a manner such that the concentration of drug is sufficient to be effective.
  • the pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient.
  • the oral dose would be about 0.5 to about 20 mg/kg.
  • parenteral administration is preferred.
  • an intravenous infusion of the peptide in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients is most effective, although an intramuscular bolus injection is also useful.
  • the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg.
  • the compounds are administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day.
  • the precise level and method by which the compounds are administered is readily determined by one routinely skilled in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect. No unacceptable toxicological effects are expected when eprosartan is administered in accordance with the present invention.
  • Focal brain ischemia Permanent or temporary cerebral focal ischemia or sham surgery was carried out under stereotaxic control in male spontaneously hypertensive rats (SHR) or in normotensive rat strain (Wistar-Kyoto), at 18 weeks of age weighing 250-330 grams, by permanent or temporary MCAO as described in detail previously (Barone FC, Price WJ, White RF, Willette RN, Feuerstein GZ (1992) Genetic hypertension and increased susceptibility to cerebral ischemia.
  • SHR spontaneously hypertensive rats
  • Wistar-Kyoto normotensive rat strain
  • the ischemic cortex i.e., the cortex ipsilateral to surgery
  • the contralateral (control) cortex was dissected from the non-ischemic contralateral hemisphere from the same rat
  • RNA samples were homogenized in an acid guanidinium thiocyanate solution and extracted with phenol and chloroform as described previously (Chomczynski P, Sacchi N (1987) Single- step method of RNA isolation by acid guanidinum thiocyanate-phenol-chloroform extraction.
  • RNA samples 40 ⁇ g/lane were electrophoresed through formaldehyde-agarose slab gels and transferred to GeneScreen Plus membranes
  • an OPN or ribosomal protein L32 cDNA was prepared as described previously (Wang XK, Louden C, Ohlstein EH, Stadel JM, Gu JL, Yue TL (1996) Osteopontin expression in platelet- derived growth factor-stimulated vascular smooth muscle cells and carotid artery after balloon angioplasty. Aterioscler Thromb Vase Biol 16: 1365-1372), and was uniformly labeled with [ ⁇ -32p]dATP (3000 Ci/mmol, Amersham Corp) using a random-priming DNA labeling kit (Boehringer Mannheim).
  • Hybridization of each probe was carried out overnight with 1x10 ⁇ cpm/ml of probe at 42 °C in 5 x SSPE (750 mM NaCl, 50 mM NaH2PO4, pH7.6, 5 mM EDTA), 50% formamide, 5 x Denhardt's solution, 2% SDS, 100 ⁇ g/ml polyA and 200 ⁇ g/ml boiled salmon sperm DNA.
  • the membranes were washed in 2 x SSPE, 2% SDS at 65 °C for 1-2 hr with a change every 30 min, then autoradiographed at -70 °C with a Cronex Lightning- Plus intensifying screen for various times depending upon the signal intensity.
  • the relative band intensities were measured using a Phosphorlmager with an ImageQuant software package (Molecular Dynamics).
  • a probe was stripped from the membranes in 10 mM Tris, pH 7.5, 1 mM EDTA, pH 8.0, 1% SDS for 20 min at 95 °C and then washed in 2 x SSPE for 10 min prior to re-hybridization with the other probe.
  • the expression of rpL32 gene is relatively constant in the present experimental conditions (Wang XK, Siren A-L, Liu Y, Yue T-L, Barone FC, Feuerstein GZ (1994) Upregulation of intercellular adhesion molecule 1 (ICAM-1) on brain microvascular endothelial cells in rat ischemic cortex.
  • IAM-1 intercellular adhesion molecule 1
  • In situ hybridization Tissue preparation, in vitro transcription, and combined in situ hybridization and immunohistochemistry was carried out as reported previously (Ellison JA, Scully SA, de Vellis J (1996) Evidence for neuronal regulation of oligodendrocyte development: cellular localization of platelet-derived growth factor a receptor and A-chain mRNA during rat cerebral cortex development. J Neurosci Res 45:28-39) with slight modifications to the in situ hybridization protocol as indicated. Tissue sections (12 ⁇ m) were incubated with the EDI antibody (Biosource International) overnight at 4 °C. Detection of the antibody was performed using the Vector Labs ABC kit according to the manufacturer's instructions using diaminobenzidine as the substrate.
  • tissue was deproteinated in 0.2 M HC1 then acetylated with 0.1 M triethanolamine (pH 8) with 0.25% acetic anhydride.
  • Antisense or sense [33p]UTP labeled OPN probes (1x10" cpm/ml) were applied to tissue and hybridized overnight at 60 °C. Posthybridization washes were modified as follows: 4 X SSC twice for 10 min each at 50 °C; 20 ⁇ g/ml RNase 30 min at 37 °C; 5 min each 2 X SSC, 1 X SSC, 0.5 X SSC at room temperature; 0.1 X SSC 20 min at 55 °C; 0.1 X SSC 5 min at room temperature. Slides were dehydrated and dried then exposed to Hyperfilm ⁇ max (Amersham) overnight. For emulsion autoradiography slides were dipped in NTB2 emulsion (Kodak) and exposed for 7 days at 4 °C.
  • Miles Vacuum Infiltration Processor
  • MPlll lO Developmental Studies Hybridoma Bank, University of Iowa, Iowa City, IA; at 1:50 dilution
  • monoclonal anti-EDl Hard Bioproducts for Science; at 1: 100 dilution
  • rabbit anti-cow GFAP DAKO; at a dilution of 1:750 or 1:20,000
  • rabbit anti-cow S-100 DAKO; at 1:20,000 dil
  • Rat C6 glial cells were obtained from American Type Cultured Collection (ATCC) and cultured in Dulbecco's modified Eagle's medium (DMEM) (GEBCO BRL) supplemented with 5% fetal bovine serum.
  • DMEM Dulbecco's modified Eagle's medium
  • Normal human astrocytes were purchased from Clonetics and cultured in an astrocyte basal medium (Clonetics) containing 5% fetal bovine serum, 20 ng/ml hEGF, 25 microg/ml insulin, 25 ng/ml progesterone, 50 microg/ml transferrin, 50 microg/ml gentamicin and 50 ng/ml amphotericin-B.
  • the human astrocytes were maintained and subcultured according to the manufacturer's specification, and applied for the cell migration assays prior to the passage 3.
  • the lower surface of the membrane was pre-coated with different concentration of recombinant rat OPN (Yue TL, McKenna PJ, Ohlstein EH, Farach- Carson MC, Butler WT, Johanson K, McDevitt P, Feuerstein GZ, Stadel JM (1994) Osteopontin-stimulated vascular smooth muscle cell migration is mediated by ⁇ 3 integrin. Exp Cell Res 214:459-464).
  • C6 cells were suspended in DMEM and human astrocytes were resuspended in astrocyte basal medium supplemented with 0.2% bovine serum albumin at a concentration of 3 x 10 ⁇ and 2 x 10 ⁇ cells per milliliter, respectively.
  • 0.2 ml of cell suspension was placed in the upper compartment of the chamber, and the lower compartment contained 0.6 ml of DMEM or astrocyte basal medium supplemented with 0.2% bovine albumin prior to use. Incubation was carried out at 37 °C in 5% CO2 for 24 h. After incubation, nonmigrated cells on the upper surface were scraped gently, and the filters were fixed in methanol and stained 10% Giemsa stain.
  • the number of cells migrated to the lower surface of the filters was either measured by optical density at 640 nm (C6 cells) or countered four high power fields ( lOO) per filter (Hidaka YT, Eda T, Yonemoto M, Kamei T (1992) Inhibition of cultured vascular smooth muscle cell migration by simvastatin (MK-7333).
  • Exp Cell Res 214:459-464 The relative number of cells for optical density measurement was evaluated in parallel with counting the cells under microscope, and percentage of cells migrated was determined. Experiments were performed in triplicate.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Cardiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'utilisation d'un antagoniste du récepteur de la vitronectine pour le traitement des accidents vasculaires cérébraux.
EP00952558A 1999-08-06 2000-08-04 Antagonistes du recepteur de la vitronectine utiles pour le traitement des accidents vasculaires cerebraux Withdrawn EP1208101A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US14756799P 1999-08-06 1999-08-06
US147567P 1999-08-06
PCT/US2000/021433 WO2001010867A1 (fr) 1999-08-06 2000-08-04 Antagonistes du recepteur de la vitronectine utiles pour le traitement des accidents vasculaires cerebraux

Publications (2)

Publication Number Publication Date
EP1208101A1 true EP1208101A1 (fr) 2002-05-29
EP1208101A4 EP1208101A4 (fr) 2003-03-19

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EP00952558A Withdrawn EP1208101A4 (fr) 1999-08-06 2000-08-04 Antagonistes du recepteur de la vitronectine utiles pour le traitement des accidents vasculaires cerebraux

Country Status (4)

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EP (1) EP1208101A4 (fr)
JP (1) JP2003506452A (fr)
AU (1) AU6523200A (fr)
WO (1) WO2001010867A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2244474T3 (es) 1999-09-29 2005-12-16 Ortho-Mcneil Pharmaceutical, Inc. Isonipecotamida para el tratamiento de trastornos mediados por integrina.
DE60208186T2 (de) 2001-04-09 2006-08-24 Ortho-Mcneil Pharmaceutical Research Inc. Chinazolin- und chinazolinähnliche verbindungen zur behandlung von integrin-vermittelten erkrankungen
JP4750360B2 (ja) 2001-10-22 2011-08-17 ザ スクリプス リサーチ インスティチュート 抗体ターゲッティング化合物
JP2012517447A (ja) 2009-02-10 2012-08-02 ザ スクリプス リサーチ インスティチュート 化学的にプログラムされたワクチン接種法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996006087A1 (fr) * 1994-08-22 1996-02-29 Smithkline Beecham Corporation Composes bicycliques
WO1997001540A1 (fr) * 1995-06-29 1997-01-16 Smithkline Beecham Corporation Antagonistes du recepteur de l'integrine
WO1997024119A1 (fr) * 1995-12-29 1997-07-10 Smithkline Beecham Corporation Antagonistes du recepteur de la vitronectine
WO1998014192A1 (fr) * 1996-10-02 1998-04-09 Smithkline Beecham Corporation Antagonistes du recepteur de la vitronectine
WO1999006049A1 (fr) * 1997-08-04 1999-02-11 Smithkline Beecham Corporation Antagonistes du recepteur de l'integrine
WO1999011626A1 (fr) * 1997-09-04 1999-03-11 Smithkline Beecham Corporation Antagonistes des recepteurs d'integrines

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996006087A1 (fr) * 1994-08-22 1996-02-29 Smithkline Beecham Corporation Composes bicycliques
WO1997001540A1 (fr) * 1995-06-29 1997-01-16 Smithkline Beecham Corporation Antagonistes du recepteur de l'integrine
WO1997024119A1 (fr) * 1995-12-29 1997-07-10 Smithkline Beecham Corporation Antagonistes du recepteur de la vitronectine
WO1998014192A1 (fr) * 1996-10-02 1998-04-09 Smithkline Beecham Corporation Antagonistes du recepteur de la vitronectine
WO1999006049A1 (fr) * 1997-08-04 1999-02-11 Smithkline Beecham Corporation Antagonistes du recepteur de l'integrine
WO1999011626A1 (fr) * 1997-09-04 1999-03-11 Smithkline Beecham Corporation Antagonistes des recepteurs d'integrines

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ELLISON J A ET AL: "OSTEOPONTIN AND ITS INTEGRIN RECEPTOR ALPHAVBETA3 ARE UPREGULATED DURING FORMATION OF THE GLIAL SCAR AFTER FOCAL STROKE" STROKE, AMERICAN HEART ASSOCIATION, DALLAS TX, US, vol. 29, no. 8, August 1998 (1998-08), pages 1698-1706, XP001029459 ISSN: 0039-2499 *
See also references of WO0110867A1 *

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WO2001010867A1 (fr) 2001-02-15
EP1208101A4 (fr) 2003-03-19
AU6523200A (en) 2001-03-05
JP2003506452A (ja) 2003-02-18

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