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WO1990003390A1 - Inhibiteurs peptidyles de l'initiation de la coagulation - Google Patents

Inhibiteurs peptidyles de l'initiation de la coagulation Download PDF

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Publication number
WO1990003390A1
WO1990003390A1 PCT/US1989/004140 US8904140W WO9003390A1 WO 1990003390 A1 WO1990003390 A1 WO 1990003390A1 US 8904140 W US8904140 W US 8904140W WO 9003390 A1 WO9003390 A1 WO 9003390A1
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Prior art keywords
peptide
amino acid
derivatized
boc
class
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PCT/US1989/004140
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English (en)
Inventor
Michael G. Pepe
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Corvas, Inc.
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Publication of WO1990003390A1 publication Critical patent/WO1990003390A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424—Serine endopeptidases (3.4.21)
    • C12N9/6437—Coagulation factor VIIa (3.4.21.21)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21021—Coagulation factor VIIa (3.4.21.21)

Definitions

  • TF is a transmembrane high affinity receptor (Ploplis et al. (1987) J. Biol. Chem. 262:9503;
  • peptides and peptide derivatives were disclosed having the ability to inhibit the proteoly ic conversion of factor X to Xa by the activated [TF:VIIa] complex.
  • the primary amino acid sequence of factor VII has also been deduced from the cloned nucleotide sequence encoding factor VII (O'Hara et al. (1987) Proc. Natl. Acad. Sci. USA 84:5158- 5162) .
  • the amino acid sequence including the probable catalytic and binding sites were predicted from the nucleotide sequence (Hagan et al. (1986) Proc. Natl. Acad. Sci. 83:2412- 2416) .
  • the compounds of the invention are used as analytical reagents and therapeutic agents to specifically inhibit the initiation of the coagulation protease cascades by [TF:VIIa] .
  • the compounds also permit accurate .in vitro and ex vivo determination whether or not activation of coagulation is attributable to the binary complex [TF:VIIa] .
  • the compounds are used as therapeutic drugs m vivo to inhibit the initiation of the coagulation system which is one of the pathogenetic mechanisms involved in thrombus formation and thrombotic related diseases, disseminated intravascular coagulation associated with septic shock and other disease processes, and certain inflammatory conditions associated with excessive activation of coagulation in the tissues.
  • the invention includes peptide and peptide derivatives that specifically inhibit blood clotting.
  • the compounds of the invention were shown to inhibit the [TF:VIIa] initiated coagulation protease cascade leading to blood clot formation.
  • Two different classes of peptides have been found to inhibit [TF:VIIa] initiated coagulation.
  • All peptides are described by amino acid sequence, using standard abbreviations known in the art, either single letter abbreviations or three-letter abbreviations. In sequences using single-letter abbreviations, the amino acids are understood to be linked by peptide bands between the ⁇ -amino group of one amino acid and the ⁇ -carboxyl of the adjacent amino acid. All amino acids described herein are L-amino acids unless specified otherwise.
  • Class I peptides have the general formula
  • R ⁇ ZGHFGVR' j where R' t is hydrogen, an amino acid, derivatized amino acid, a peptide, a derivatized peptide, or a protein; R* 2 is hydroxyl, an amino acid, a derivatized amino acid, a peptide, a derivatized peptide, or a protein; Z is Valine or Glycine.
  • a derivatized amino acid or derivatized peptide is one wherein functional side or end groups are protected by reaction with a reactant to form an adduct or compound therewith.
  • amino acid derivatives or peptide derivatives are known including, for example, amides, esters, t-butoxy carbonyls, carbobenzoxys, tosyls, benzyls, 7-amino 4-methyl coumarins and the like, all as well-known in the art.
  • sequence VGHFGV is found at position 372-377 in the amino acid sequence of factor VII.
  • Class II peptides have the general formula
  • R ⁇ SDHTGTKRSCR' j where R'., and R' 2 are defined as for class I peptides.
  • the sequence SDHTGTKRSC is found at position 103-112 in the amino acid sequence of factor VII.
  • R 1 is cysteine
  • the resultant peptide specifies the amino acid sequence at position 102-112 of factor VII. This undecameric sequence spans the greater part of a loop structure within the native peptide structure of factor VII, as tentatively depicted by
  • modifications of the defined class I and class II peptides can be made, the modified peptides retaining activity as inhibitors of blood clotting.
  • modifications include, for example, amino acid substitutions and utilization of different amino acid isomeric forms, e.g. D-amino acids. Not all substitutions or deletions would be expected to, nor do they yield inhibitors. However, those of ordinary skill in the art will recognize that certain substitutions are more likely to yield equivalent activity than others. Substituents with similar properties, for example, hydrophobic side chains, are more likely to yield active equivalents when replacing amino acids with similar side chains. Substitution of negatively charged for negatively charged, positively charged for positively charged, aromatic for aromatic all have a higher likelihood of success than nonsimilar substitutions.
  • Factor X activation Activity in blood clotting inhibition is measured by an assay for factor X activation.
  • Purified factor X when activated (converted to Xa) hydrolyses a chro ogenic substrate S-2222 N-Benzoyl-L-Isoleucyl-L-Glutamyl-L-Arginine-p- Nitroanilide Hydrochloride (Helena Labs, Beaumont, Texas) . Hydrolysis of S-2222 leads to a color change measurable by a change in absorbance at 405 nm.
  • Activation of factor X depends in turn on formation of an active [TF:VIIa] complex.
  • factor VII was purified as described by Fair, D.S. (1983) Blood 62.:784.
  • Tissue factor was provided by a cell line, J82, derived from human bladder carcinoma, and publicly available from American Type Culture Collection, Rockville, MD, under accession No. ATCC HTBl. It has been previously demonstrated that factor VII and factor Vila bind to and are activated on the surface of J82 cells (Fair, D.S. et al. (1987) J. Biol. Chem. 162.:11692. Factor X was purified as described by Schwartz, B.S. et al. (1981) J. Clin. Invest. .67:1650.
  • purified factor VII or Vila binds to TF forming an active [TF:VIIa] complex which in turn acts to convert factor X to Xa by specific proteolysis.
  • Factor Xa then hydrolyzes S-2222, yielding a change in absorbance at 405 nm.
  • the foregoing steps are considered the initial steps in the coagulation protease cascade that results in blood clot (thrombus) formation in whole blood. Inhibitors in the assay therefore act as clotting inhibitors.
  • class I and class II peptides are considered to inhibit the initial binding of TF with factor VII, preventing formation of an active [TF:VIIa] complex. Inhibition of S-2222 conversion in the assay is therefore considered to be the consequence of inhibition of the initial TF binding to factor VII. Inhibition is considered to be reversible and competitive for factor VII, either by directly interacting with TF or factor X or both.
  • Class I and class II peptides where R 1 ., is hydrogen and R* 2 is hydroxyl are not known to have any biological activity other than the activity disclosed. They are therefore specific inhibitors of [TF:VIIa] initiated blood coagulation. The possibility that other biological activity may be provided by proper choice of R', and/or R' 2 will be understood in the art. Multi-functional class I and class II peptides can be constructed by combining the core sequences with R', and/or R* 2 peptides having known activity in themselves.
  • Peptides of class I and class II and pharmaceutically acceptable salts thereof are useful in the treatment of thrombosis, disseminated intravascular coagulation, septic shock and inflammation of cellular immune mediated diseases.
  • the compounds of class I and class II and pharmaceutically acceptable salts thereof may be used alone or mixed with a pharmaceutically acceptable carrier.
  • Such compounds or salts can be administered to patients parenterally, for example subcutaneously, intravenously or intraperitoneally.
  • Such compounds can be administered by intranasal instillation or by application to mucous membranes such as those of the sublingual region of the mouth or the nasal or bronchial mucosa as a spray, dry particle suspension or solution in water or saline solution.
  • the peptide was deprotected and cleaved from the PAM support by standard protocols and reagents including HF cleavage [anisole:resin:HF (1:1:10)] for 60 min at 0°C. Approximately 20-30 mg of product was purified on a Vydac C-18 column eluted with 10-40% (v/v) acetonitrile gradient, dried under vacuo. The product was used for analysis by dissolving it in water or desired aqueous solution.
  • N-Boc-L-Leucine PAM resin was coupled with the following amino acid derivatives starting with N- ⁇ -Boc- N-e-(2-ChloroCBZ)-L-Lysine and sequentially followed by N- ⁇ - Boc-L-Glutamine, N-Boc-L-Leucine, N- ⁇ -Boc-N-Indole-Formyl-L- Tryptophan, N-Boc-L-Glutamic acid-gamma-Benzyl ester, N-Boc- L-Isoleucine, N-Boc-0-(2-BromoCBZ)-L-Tyrosine, N- ⁇ -Boc-L- Glutamine, N-Boc-O-Bzl-Serine, N-Boc-L-Valine, N- ⁇ -Boc-N- Tosyl-L-Arginine, N-Boc-O-Bzl
  • N-Boc-Glycine N-Boc-L-Phenylalanine, N- ⁇ -Boc-Im-cbz-L-
  • N-Boc-S-4-Methylbenzyl-L-Cysteine PAM support resin was coupled with N-Boc-L-Proline and sequentially coupled with N- Boc-L-Phenylalanine, N-Boc-L-Proline, N-Boc-L-Alanine, N- ⁇ - Boc-N-Tosyl-L-Arginine, N-Boc-L-Leucine, N-Boc-L-Leucine, N- Boc-L-Valine, N-Boc-Glycine, N-Boc-L-Proline, N-ct-Boc-N-Tosyl- L-Arginine, N-Boc-L-Proline, N-Boc-L-Glutamic acid-gamma- Benzyl ester, N-Boc-O-Bzl-L-Serine, N- ⁇ -Boc-N-Tosyl-
  • N-Boc-Glycine PAM resin was coupled sequentially with the following amino acid derivatives starting with N-Boc-S-acetamidomethyl-L-cysteine, N-Boc-O- Bzl-L-Serine, N- ⁇ -Boc-N-Tosyl-L-Arginine, N- ⁇ -Boc-N-e-(2- ChloroCBZ)-L-Lysine, N-Boc-O-Bzl-L-Threonine, N-Boc-Glycine, O-Boc-O-Bzl-L-Threonine, N- ⁇ -Boc-N-im-Cbz-L-Histidine, N-Boc- L-Aspartic Acid- ⁇ -Benzyl ester, N-Boc-O-Bzl-L-Serine, N-Boc- S-acetamidomethyl-L-
  • the linear peptide (synthesized as described in Example 5(a)) was cy ⁇ lized through disulfide bond formation.
  • the linear peptide (0.05 mmol) was dissolved in 350 ⁇ l of methanol: ater (1:6) at room temperature and the solution was stirred while adding 50 ⁇ l of ImM iodine in methanol dropwise for one hour at 4°C. The solution was stirred at 4°C for 2 days. The reaction was completely quenched with 1M sodium thiosulfate, lyophilized and then desalted by HPLC.
  • the cyclization procedure is detailed by Stewart and Young (1984) in Solid Phase Peptide Synthesis. Pierce Chemical Co., Rockford, IL.
  • N-Boc-S-acetamidomethyl-L-cysteine PAM resin was coupled sequentially with the folloing amino acid derivatives starting with N-Boc-O-Bzl-L-Serine, N- ⁇ -Boc-N- Tosyl-L-Arginine, N- ⁇ -Boc-N-e-(2-ChloroCBZ)-L-Lysine, N-Boc- O-Bzl-L-Threonine, N-Boc-Glycine, N-Boc-0-Bzl-L-Threonine,N- -Boc-N-im-Cbz-L-Histidine, N-Boc-L-Aspartic Acid- ⁇ -Benzyl ester, N-Boc-O-Bzl-L-Serine, N-Boc-O-Bzl-L-Serine, N-Boc-L-Aspartic Acid- ⁇ -Benzyl
  • the linear peptide (synthesized as described in Example 6(a)) was cyclized through disulfide bond formation essentially as described in Example 5(b).
  • peptides includingthose synthesized essentially as described in Examples 1-6, were tested for inhibitor activity. Using the assay system described in the legend of Table 1, the peptides listed therein were assayed for inhibitory potency at concentrations up to ImM. From the results of inhibitory activity of the peptides of Examples 2- 4 (Class I peptides) , a series of overlapping hexapeptides within the sequence TVGHFGVYTRV was synthesized essentially as described in Example 1. The peptides were assayed for inhibitory activity with results shown in Table 2. Maximal inhibitory activity was observed in peptides having a core TABLE 1
  • Peptides which were 6 amino acids in length were synthesized based upon the amino acid sequences of peptides of Examples 2-4 which inhibit [TF:VIIa]-initiated activation of factor X (Table 1) .
  • the peptides were identified for synthesis by moving a 6 mer bracket along the amino acid sequence TVGHFGVYTRV. Activity was measured as described in Table 1.
  • peptides having the foregoing core plus additional amino acids, peptides or proteins at the amino or carboxyl ends are also active as inhibitors. Therefore, peptides of class I, R'. j ZGHFGVR'.,, where Z is V or G and R' t is hydrogen, an amino acid, derivatized amino acid, a peptide, a derivatized peptide or a protein, and R' 2 is OH, an amino acid, a derivatized amino acid, a peptide, a derivatized peptide or a protein are inhibitors of the present invention.
  • the general formulae of peptides of class II can be shortened to include an octapeptidyl core, i.e., R' 1 DHTGTKRSR , 2 , where R ⁇ is hydrogen, an amino acid, derivatized amino acid, a peptide, a derivatized peptide or a protein, and R' 2 is OH, an amino acid, a derivatized amino acid, a peptide, a derivatized peptide or a protein, are inhibitors of the present invention.
  • class II peptides had the shortened core formula R ⁇ DHTGTKRSR ⁇ where R 1 ., is L- serine and R' 2 is L-cysteine. Moreover, it " was also preferred that the N-terminal amino acid be acetylated and the C- terminal amino acid be in the amide form.
  • the ten member core sequence shown to have inhibitory activity in Table 1 was contained within the peptide GCSDHTGTKRSCG (Table 4) which was synthesized both as a linear and a cyclized peptide.
  • This peptide is a class II inhibitor, having the formula R ⁇ SDHTGTKRSCR' 2 described above where R 1 , is Gly-Cys and R' 2 is Gly.
  • R 1 is Gly-Cys
  • R' 2 is Gly.
  • both the linear and cyclic forms of this peptide were biologically active.
  • the activity of the cyclic form which was cyclized by virtue of disulfide bond formation, was approximately 10 times greater than that of the linear form of the peptide.
  • the ten-member core sequence -SDHTGTKRSC- was extended to include at the N-terminal end a pentapeptide and a cysteine at the carboxyl end of the molecule.
  • Relative potency is expressed as megaunits (MU) , where one unit is equal to the inverse of the molar concentration at 5% inhibition of clotting as assessed by inhibition of factor X activation. Quantitation of inhibition was performed in a linked enzyme chromogenic assay using purified factor VII (Fair (1983) Blood 62:784—791) and factor X (Schwartz et al. (1981) J. Clin. Invest..67:1650-1658), TF positive cells (J82) and chromogenic substrate S-2222 (Helena Labs, Beaumont, Texas) .
  • MU megaunits
  • the peptides were simultaneously incubated with 1 nM factor VII, 100 nM factor X, 20mM CaC12, 1X105 J82 cells (American Type Culture Collection, Rockville, MD, under accession no. ATCC HTBl) and 2 mM S-2222 in a total volume of 225 ⁇ L.
  • the rate of conversion of factor X to Xa was monitored kinetically by the change in absorbance of the chromogenic product of S-2222 at 405 n .
  • peptide containing fifteen amino acids was synthesized in both a linear and cyclic form. Both the linear and cyclic forms of this peptide were biologically active in the clotting assay assessed by inhibition of factor X activation.
  • cyclic peptides having class II inhibitory activity are contemplated in this invention.
  • Such cyclic peptides are patterned after the cyclic peptides exemplified in this invention and include peptides wherein the number of amino acids comprising the peptide are increased in order to effectively widen or lengthen the resultant loop or to add additional loops.
  • Cyclic peptides of this type are class II inhibitors of coagulation.
  • the peptides were derivatized such that the functional groups of the terminal amino acids were protected through chemical linkage.
  • the N- terminal amino acid was acetylated and the C-terminal amino acid was converted into an amide.
  • class I and class II peptides can be synthesized essentially as described in Examples 1-6, or by other suitable techniques of peptide synthesis available to the art.

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Abstract

Deux classes de peptides et de dérivés de peptides inhibent spécifiquement la série de réactions en chaîne initiées par [TF:VIIa] qui mènent à la coagulation sanguine. Les peptides de la classe I ont la formule générale R'1ZGHFGVR'2, alors que les peptides de la classe II contiennent la séquence centrale -DHTGTKRS', les peptides des deux classes pouvant être linéaires ou cycliques. L'invention concerne l'utilisation de ces inhibiteurs comme réactifs de diagnostic, comme réactifs analytiques et comme médicaments.
PCT/US1989/004140 1988-09-23 1989-09-22 Inhibiteurs peptidyles de l'initiation de la coagulation WO1990003390A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US24881788A 1988-09-23 1988-09-23
US248,817 1988-09-23
US40859589A 1989-09-20 1989-09-20
US408,595 1989-09-20

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991007432A1 (fr) * 1989-11-13 1991-05-30 Board Of Regents, The University Of Texas System Peptides antihemostatiques du facteur vii
EP0446797A2 (fr) * 1990-03-13 1991-09-18 BEHRINGWERKE Aktiengesellschaft Peptides synthétiques comportant des séquences du facteur VIIa et leur utilisation
WO1995000541A1 (fr) * 1993-06-18 1995-01-05 Hafslund Nycomed A/S Peptides derives du facteur vii
WO1996018653A1 (fr) * 1994-12-15 1996-06-20 Nycomed Imaging As Disulfure-cyclo-[h-cys-glu-gln-tyr-cyr-oh] et son utilisation pour le traitement des troubles de coagulation sanguine
WO1996018654A1 (fr) * 1994-12-15 1996-06-20 Nycomed Imaging As Fragment 82-128 du facteur vii et son utilisation pour le traitement des troubles de la coagulation sanguine
US5788965A (en) * 1991-02-28 1998-08-04 Novo Nordisk A/S Modified factor VII
US5817788A (en) * 1991-02-28 1998-10-06 Zymogenetics, Inc. Modified factor VII
US5833982A (en) * 1991-02-28 1998-11-10 Zymogenetics, Inc. Modified factor VII
US5861374A (en) * 1991-02-28 1999-01-19 Novo Nordisk A/S Modified Factor VII
WO1999013062A1 (fr) * 1997-09-09 1999-03-18 Nycomed Imaging As Fragments de facteur vii, leurs analogues, et leur utilisation dans le traitement de troubles lies a la coagulation du sang
WO1999013063A1 (fr) * 1997-09-09 1999-03-18 Nycomed Imaging As Fragments du facteur vii et leurs analogues, utilisation dans le traitement des troubles dus aux caillots sanguins
US5997864A (en) * 1995-06-07 1999-12-07 Novo Nordisk A/S Modified factor VII
US6039944A (en) * 1992-02-28 2000-03-21 Zymogenetics, Inc. Modified Factor VII
EP0987274A1 (fr) * 1998-09-15 2000-03-22 Hoechst Marion Roussel Deutschland GmbH Inhibiteurs du facteur VIIa
US7084109B2 (en) 1999-07-02 2006-08-01 Genentech, Inc. FVIIa antagonists
US7164002B2 (en) 2002-02-06 2007-01-16 Genentech, Inc. FVIIa antagonists
WO2011036443A3 (fr) * 2009-09-22 2011-10-06 Ximmune Ab Polypeptides et leurs utilisations
WO2017121436A1 (fr) 2016-01-15 2017-07-20 Rigshospitalet Imagerie par tep quantitative de l'expression du facteur tissulaire employant un facteur vii inhibé à site actif marqué au 18f
WO2018091058A1 (fr) 2016-11-17 2018-05-24 Rigshospitalet Facteur vii inhibé par le site actif marqué par 177-lu

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Biochemistry, Vol. 27, 1988, THIM, "Amino acid sequence and post translational modifications of human factor VIIa from plasma and transfected baby hamster kidney cells", pages 7785-7793, see page 7789, Figure 3 and page 7791, col. 2. *
Cell, Vol. 50, 03 July 1987, J. MORRISSEY, "Molecular cloning of the cDNA for tissue factor, the cellular receptor for the initiation of the coagulation protease cascade", pages 129-135, see the entire document. *
Federation Proceedings, Vol. 47, 15 September 1988, Thrombosis and Thrombolysis (552-557), N. PAPS, "Functional sites on human tissue factor", see col. 1, No. 552. *
Proc. Natl. Acad. Sci. USA, Vol. 83, April 1986, F. HAGEN, "Characterization of cDNA coding for human factor VII", pages 2412-2416, see page 2414, Fig. 2. *
Proc. Natl. Acad. Sci. USA, Vol. 84, August 1987, O'HARA, "Nucleotide sequence of the gene coding for human factor VII, a vitamin K-dependent protein participating in blood coagulation", pages 5158-5162, see the entire document. *
See also references of EP0391999A4 *

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991007432A1 (fr) * 1989-11-13 1991-05-30 Board Of Regents, The University Of Texas System Peptides antihemostatiques du facteur vii
EP0446797A2 (fr) * 1990-03-13 1991-09-18 BEHRINGWERKE Aktiengesellschaft Peptides synthétiques comportant des séquences du facteur VIIa et leur utilisation
EP0446797A3 (en) * 1990-03-13 1993-04-07 Behringwerke Aktiengesellschaft Synthetic peptides containing factor viia sequences and their use
US6183743B1 (en) 1991-02-28 2001-02-06 Zymogenetics, Inc. Modified factor VII
US6168789B1 (en) 1991-02-28 2001-01-02 Zymogenetics, Inc. Modified factor VII
US5788965A (en) * 1991-02-28 1998-08-04 Novo Nordisk A/S Modified factor VII
US5817788A (en) * 1991-02-28 1998-10-06 Zymogenetics, Inc. Modified factor VII
US5833982A (en) * 1991-02-28 1998-11-10 Zymogenetics, Inc. Modified factor VII
US5861374A (en) * 1991-02-28 1999-01-19 Novo Nordisk A/S Modified Factor VII
US6039944A (en) * 1992-02-28 2000-03-21 Zymogenetics, Inc. Modified Factor VII
US5962418A (en) * 1993-06-18 1999-10-05 Nycomed Imaging A/S Factor VII-derived peptides
WO1995000541A1 (fr) * 1993-06-18 1995-01-05 Hafslund Nycomed A/S Peptides derives du facteur vii
WO1996018654A1 (fr) * 1994-12-15 1996-06-20 Nycomed Imaging As Fragment 82-128 du facteur vii et son utilisation pour le traitement des troubles de la coagulation sanguine
US5948759A (en) * 1994-12-15 1999-09-07 Nycomed Imaging As Factor VII fragment 82-128 and its use in blood-clotting disorders
US5962408A (en) * 1994-12-15 1999-10-05 Nycomed Imaging As Disulphide-cyclo- H-Cys-Glu-Gln-Tyr-Cys-OH!, and its use in blood-clotting disorders
WO1996018653A1 (fr) * 1994-12-15 1996-06-20 Nycomed Imaging As Disulfure-cyclo-[h-cys-glu-gln-tyr-cyr-oh] et son utilisation pour le traitement des troubles de coagulation sanguine
US5997864A (en) * 1995-06-07 1999-12-07 Novo Nordisk A/S Modified factor VII
WO1999013063A1 (fr) * 1997-09-09 1999-03-18 Nycomed Imaging As Fragments du facteur vii et leurs analogues, utilisation dans le traitement des troubles dus aux caillots sanguins
WO1999013062A1 (fr) * 1997-09-09 1999-03-18 Nycomed Imaging As Fragments de facteur vii, leurs analogues, et leur utilisation dans le traitement de troubles lies a la coagulation du sang
EP0987274A1 (fr) * 1998-09-15 2000-03-22 Hoechst Marion Roussel Deutschland GmbH Inhibiteurs du facteur VIIa
WO2000015658A1 (fr) * 1998-09-15 2000-03-23 Aventis Pharma Deutschland Gmbh INHIBITEURS DU FACTEUR VIIa
US6287794B1 (en) 1998-09-15 2001-09-11 Aventis Pharma Deutschland Gmbh Factor Vlla inhibitors
JP2002524571A (ja) * 1998-09-15 2002-08-06 アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング ＶＩＩａ因子阻害剤
CZ300249B6 (cs) * 1998-09-15 2009-04-01 Sanofi - Aventis Deutschland GmbH Inhibitory faktoru VIIa, zpusob jejich prípravy a farmaceutický prostredek, který je obsahuje
US7084109B2 (en) 1999-07-02 2006-08-01 Genentech, Inc. FVIIa antagonists
US7164002B2 (en) 2002-02-06 2007-01-16 Genentech, Inc. FVIIa antagonists
WO2011036443A3 (fr) * 2009-09-22 2011-10-06 Ximmune Ab Polypeptides et leurs utilisations
WO2017121436A1 (fr) 2016-01-15 2017-07-20 Rigshospitalet Imagerie par tep quantitative de l'expression du facteur tissulaire employant un facteur vii inhibé à site actif marqué au 18f
WO2018091058A1 (fr) 2016-11-17 2018-05-24 Rigshospitalet Facteur vii inhibé par le site actif marqué par 177-lu

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AU4338689A (en) 1990-04-18
EP0391999A1 (fr) 1990-10-17

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