WO2018024818A1 - Composé pour le traitement d'une maladie associée à une dérégulation de la voie du complément alternative - Google Patents

Composé pour le traitement d'une maladie associée à une dérégulation de la voie du complément alternative Download PDF

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Publication number
WO2018024818A1
WO2018024818A1 PCT/EP2017/069633 EP2017069633W WO2018024818A1 WO 2018024818 A1 WO2018024818 A1 WO 2018024818A1 EP 2017069633 W EP2017069633 W EP 2017069633W WO 2018024818 A1 WO2018024818 A1 WO 2018024818A1
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Prior art keywords
compound according
compound
substituted
procfd
following structure
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PCT/EP2017/069633
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German (de)
English (en)
Inventor
Eloed KOERTVÉLY
Marius Ueffing
Sascha Dammeier
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Eberhard Karls Universitaet Tuebingen Medizinische Fakultaet
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Publication of WO2018024818A1 publication Critical patent/WO2018024818A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P37/02—Immunomodulators
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96433—Serine endopeptidases (3.4.21)

Definitions

  • a compound for the treatment of a disease associated with a desegregation of the alternative complement pathway A compound for the treatment of a disease associated with a desegregation of the alternative complement pathway
  • the present invention relates to a novel compound for the treatment and / or prophylaxis and / or diagnosis of a disease associated with a deregulation, preferably a dysregulated activation, more preferably a hyperactivation of the alternative complement pathway. It also relates to the use of the novel compound for complexing and / or isolating and / or localizing and / or quantifying proCFD-activating compounds in / from a biological sample.
  • the complement system is a system of plasma proteins that is used in the course of
  • Immune response can be activated. It is part of the innate immune system.
  • the human complement system consists of more than 30 proteins, which are dissolved in the blood plasma or cell-bound. They defend against micro-organisms, but also have strong cell-destroying properties and may, if they are unregulated, be responsible for tissue damage in the course of many diseases.
  • CFD complement factor D
  • adipsin or C3-proactivator convertase CFD
  • CFD complement factor D
  • adipsin or C3-proactivator convertase CFD is a serine protease that is predominantly synthesized in adipose tissue and secreted into the bloodstream.
  • CFD can be found in various tissues.
  • CFD cleaves the complement factor B.
  • CFD arises from a protein precursor with an N-terminal signal peptide.
  • This signal peptide is cleaved during the secretory pathway and the enzyme is formed as an inactive proenzyme (proCFD) or Zymogen.
  • proCFD is converted to the mature and active form, ie the CFD, by the removal of six N-terminal amino acids.
  • MASPs mannose-binding lectin serine peptidases
  • CFD complement factor B
  • CFD has elastase activity.
  • the plasma concentrations of CFD are very low and are at 1 -2 ⁇ g ml, making CFD the lowest concentration complement factor, significantly lower than that of complement C3, which is 1-2 mg / ml, or complement factor B , which is 200 ⁇ g ml.
  • CFD is therefore the rate-limiting enzyme in the alternative pathway of the complement system.
  • Adipsin is an adipokine that better cell function in diabetes, Cell, 158 (1): 41-53, describe a connection between the alternative pathway of the complement system and the development of diabetes mellitus type 2.
  • CFD CFD
  • Complement pathway can lead to autoimmune diseases, for example, to age-related macular degeneration (AMD); see. Weber et al. (2014) The system of age-related macular degeneration. Dtsch Cardioebl Int 1 1 1, pp. 133-138, on renal diseases manifesting as atypical hemolytic uremic syndrome (aHUS); see. Wong et al. (2013), Complement therapy in atypical haemolytic uraemic syndrome (AHUS). Mol Immunol 56, p. 199-212, or else to C3 glomerulopathy; see. Noris et al.
  • Lampalizumab Roche / Genentech, is an antigen binding fragment of a humanized monoclonal antibody that binds CFD. He is currently being tested for the dry form of AMD and is in clinical phase 3. It has been shown that lampalizumab does not discriminate between the active and inactive (pro) forms of CFD. and thus eliminates both forms. This suggests that the use of lampalizumab in humans will be associated with a variety of side effects.
  • - n is an integer from 0 to 5;
  • R1 is selected from the group consisting of: H, detectable marker;
  • R2 is selected from the group consisting of: substituted or unsubstituted aryl each having a MW of ⁇ 200 Da, substituted or unsubstituted aryl each having a MW of ⁇ 200 Da, a side chain of a natural or synthetic amino acid;
  • R3 is selected from the group consisting of: substituted or unsubstituted alkyl each having an MW of ⁇ 300 Da, substituted unsubstituted
  • tes aryl each having a MW of ⁇ 300 Da, preferably a side chain of a natural or synthetic amino acid
  • - R4 and R5 are independently selected from the group consisting of: substituted or unsubstituted aryl each having a MW> 70 kDa and ⁇ 300 Da, substituted or unsubstituted alkyl each having a MW> 70 kDa and ⁇ 300 Da.
  • this compound corrects the corrected
  • the inactive pool of potential proCFD activators remains unchanged. Because of this high selectivity, the compound of the invention can be specifically intervened in disease-causing processes. The complement system is still functional and is available for alien defense. The compound of the invention therefore has a particularly favorable side effect profile.
  • the compound of the invention therefore represents a promising new approach to the treatment of diseases associated with the deregulation of the alternative complement pathway.
  • the provision of a detectable marker leads to the obtaining of a compound by means of which the proCFD activation as well as the activating enzymes can be observed by means of imaging methods.
  • the use of the compound with a detectable marker according to the invention is possible both in vitro and in vivo, ie in the living organism.
  • the compound according to the invention furthermore represents a tool for isolating the proCFD-activating enzymes.
  • the compound according to the invention after sufficient incubation in a biological sample which contains or contains proCFD and the activating enzymes, for example blood plasma, from Sample removed. This can be done by methods known in the art, for example.
  • a catcher molecule which is directed against a portion of the compound of the invention.
  • proCFD-activating enzymes are present in complex with proCFD. They can be removed from the complex and investigated by methods known to those skilled in the art. Thus, a quantitative protease profile of the biological samples can be generated, which can be of prognostic and diagnostic value.
  • the spacer may preferably consist of natural or synthetic amino acids or amino acid derivatives.
  • Preferred spacers have the following structure, wherein the one-letter code is used:
  • Abu-RG Abu-PRG and Abu-PPRG, where "Abu” is a non-natural amino acid with an ethyl side chain, preferably homo-alanine;
  • the compound according to the invention has the following structure:
  • - Ar is a substituted or unsubstituted aryl each having a MW> 70 kDa and ⁇ 300 Da.
  • R6, R7 and R8 are each independently a side chain of a natural or synthetic amino acid.
  • this embodiment leads to particular
  • the compound R6 is a proline radical
  • / or R7 is an arginine radical
  • / or R8 is a glycine radical
  • the detectable marker is selected from the group consisting of: biotin, biotinyl residue, radioactive marker, fluorescent marker, PET tracer.
  • the compound has the following structure:
  • the compound developed by the inventors has the following structure:
  • the inventors have carried out their experiments. They found that this compound is well suited for the regulation and in particular inhibition of proCFD activation.
  • the biotin residue provided at one end here: left
  • the compound can be well detected both in vitro and in vivo in the biological sample.
  • Another object of the present invention relates to the compound of the invention or its use for the treatment and / or prophylaxis and / or diagnosis of a disease associated with a deregulation, preferably a dysregulated activation, more preferably a hyperactivation of the alternative complement pathway.
  • the compound of the invention interacts with the proCFD-activating enzymes and - preferably - inhibits them.
  • the compound of the invention interacts or preferably inhibits the processing of proCFD in a mechanistic manner. This is advantageous since it is to be expected that proCFD will be activated not only by a single complement factor or a single enzyme but by various factors and by different pathways.
  • the compound according to the invention can interact with, and preferably inhibit, several or possibly all proCFD-activating enzymes.
  • deregulation is understood to mean a dysregulation of the cascade of the alternative complement pathway.
  • dysregulated activation is meant an impaired activation of the alternative complement pathway, in particular a disturbed activation of proCFD in CFD.
  • hyperactivation is meant, according to the invention, an activation of the alternative complement path that goes beyond the normal state.
  • the disease is an autoimmune disease.
  • the disease is further preferably selected from the group consisting of: age-related macular degeneration (AMD), kidney disease, in particular atypical hemolytic anemic syndrome (aHUS) and C3 glomerulopathy.
  • AMD age-related macular degeneration
  • aHUS atypical hemolytic anemic syndrome
  • C3 glomerulopathy C3 glomerulopathy
  • Another object of the present invention relates to a pharmaceutical or diagnostic composition having the compound of the invention in a pharmaceutically or diagnostically effective concentration and a pharmaceutically or diagnostically acceptable formulation.
  • compositions are well known in the art. For example, reference is made to the paper by Kibbe A. (2003), Handbook of Pharmaceutical Excipients, 4th Edition, American Pharmaceutical Association and Pharmaceutical Press. The properties, advantages, further developments and embodiments of the compound according to the invention apply correspondingly to the pharmaceutical and diagnostic composition according to the invention.
  • Another object of the present invention relates to the use of the compound according to the invention in vitro for inhibiting the activation of proCFD in a biological sample.
  • a “biological sample” may be any composition that includes or is believed to have the elements and factors of the alternative complement pathway, such as complement factors, cofactors, etc.
  • a preferred biological sample is a blood plasma sample of an individual, for example of any Mammalier, including a human.
  • the compound according to the invention is used for the complexation and / or isolation and / or localization and / or quantification of proCFD-activating compounds in / from a biological sample.
  • Another object of the present invention relates to a method for the treatment and / or prophylaxis and / or diagnosis of a disease associated with a desegulation, preferably a dysregulated activation, more preferably a Hyperoxidie- tion of the alternative complement pathway, the administration of the compound of the invention and / or the composition of the invention in an individual, for example any mammal, including a human.
  • FIG. 1 Chemical structure of an example of an activity-based probe according to the invention, oriented on the activator (s) of proCFD.
  • FIG. 2 The inactive proenzyme of the human complement factor D (proCFD) is activated by the cleavage of the six N-terminal amino acids. Several serine proteases are able to catalyze this step in vitro. The difference in the isoelectric points of the active versus inactive forms allows the detection of the activation process by means of isoelectric focusing. Inactive proCFD was incubated with human blood plasma. The physiological activator is present in the plasma, therefore proCFD is activated rapidly (lane # 6, see the band towards the anode (+)).
  • proCFD human complement factor D
  • Fig. 1 is the structure of an example of an activity-based probe
  • the empirical formula is C 5 4H82N 15 0iiPS.
  • the molecular weight is 1 179.5777 daltons. It has a targeting element that corresponds to the sequence of the N-terminal pro-peptide (APPRGR) of CFD. Shorter fragments, such as PRGR, have been found to be sufficient to achieve complete inhibition of the proCFD activator (s).
  • the C-terminal arginine (R) has been replaced by a functional group often referred to as
  • Warhead (engl., “Warhead”) is called. This arginine mimetic, a diphenylphosphonate, covalently modifies target enzymes in an activity-dependent manner.
  • the biotin tag attached to the probe can be used in a variety of applications, such as in visualizing the probe in histochemical studies or using streptavidin as a biotin-directed capture molecule in a covalently-affinity-purified affinity purification Enzymes from different organic samples. It is also possible to identify and quantify the amount of bound protein using standard biochemical methods.
  • proCFD By transient transfection of adherently growing HEK-293 cells (human embryonic kidney cells) proCFD was recovered. 20 ⁇ M EDTA plasma from healthy blood donors were mixed with 1 ⁇ of the compound of the invention in different Concentrations (1, 6 mM, 0.16 mM, 0.016 mM, 0.0016 mM) preincubated for 10 minutes at 37 ° C, then added to proCFD and incubated for a further 6 hours. The reaction was stopped by acetone precipitation and the activation of proCFD visualized by means of isoelectric focusing and subsequent detection on an immunoblot using a CFD antibody; see Figure 2.
  • the compound of the present invention is useful for the treatment, prophylaxis and diagnosis of a disease associated with desegregulation, dysregulated activation and hyperactivation of the alternative complement pathway.

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  • Engineering & Computer Science (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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  • Gastroenterology & Hepatology (AREA)
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  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un composé pour le traitement et/ou la prophylaxie et/ou le diagnostic d'une maladie associée à une dérégulation, de préférence à une activation dysrégulée, de façon plus préférée à une hyperactivation de la voie du complément alternative. L'invention concerne également une composition pharmaceutique et diagnostique contenant le composé selon l'invention. L'invention concerne également l'utilisation du composé selon l'invention in vitro pour l'inhibition de l'activation de pro CFD (facteur du complément D) dans un échantillon biologique.
PCT/EP2017/069633 2016-08-03 2017-08-03 Composé pour le traitement d'une maladie associée à une dérégulation de la voie du complément alternative WO2018024818A1 (fr)

Applications Claiming Priority (2)

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DE102016114392.8 2016-08-03
DE102016114392.8A DE102016114392A1 (de) 2016-08-03 2016-08-03 Verbindung zur Behandlung einer mit einer Desregulierung des alternativen Komplementweges assoziierten Erkrankung

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2676962A1 (fr) * 2012-06-21 2013-12-25 Universität Ulm Dérivés d'esters de diaryle 1-aminoalkylphosphonate, procédé de préparation de dérivés d'ester de diaryle 1-aminoalkylphosphonate et leur application

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* Cited by examiner, † Cited by third party
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KR20160118368A (ko) * 2014-02-25 2016-10-11 아칠리온 파르마세우티칼스 인코포레이티드 보체 매개된 장애의 치료를 위한 에터 화합물

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2676962A1 (fr) * 2012-06-21 2013-12-25 Universität Ulm Dérivés d'esters de diaryle 1-aminoalkylphosphonate, procédé de préparation de dérivés d'ester de diaryle 1-aminoalkylphosphonate et leur application

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
GLOVER G I ET AL: "Synthetic peptide inhibitors of complement serine proteases-I. Identification of functionally equivalent protease inhibitor sequences in serpins and inhibition of C1s and D", MOLECULAR IMMUNOLOGY, PERGAMON, GB, vol. 25, no. 12, 1 December 1988 (1988-12-01), pages 1261 - 1267, XP023681522, ISSN: 0161-5890, [retrieved on 19881201], DOI: 10.1016/0161-5890(88)90040-5 *
HOLERS, THE SPECTRUM OF COMPLEMENT ALTERNATIVE PATHWAY-MEDIATED DISEASES, IMMUNOLOGICAL REVIEWS, vol. 223, 2008, pages 300 - 316
JAMES C. POWERS ET AL: "Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases", CHEMICAL REVIEWS, vol. 102, no. 12, 1 December 2002 (2002-12-01), pages 4639 - 4750, XP055138340, ISSN: 0009-2665, DOI: 10.1021/cr010182v *
JOOSSENS J ET AL: "Development of Irreversible Diphenyl Phosphonate Inhibitors for Urokinase Plasminogen Activator", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 47, no. 10, 1 January 2004 (2004-01-01), pages 2411 - 2413, XP002422331, ISSN: 0022-2623, DOI: 10.1021/JM0499209 *
KIBBE A.: "Handbook of Pharmaceutical Excipients", 2003, AMERICAN PHARMACEUTICAL ASSOCIATION AND PHARMACEUTICAL PRESS
LO ET AL.: "Adipsin is an adipokine that improves better cell function in diabetes", CELL, vol. 158, no. 1, 2014, pages 41 - 53
MAMIDI ET AL.: "Neutralization of membrane complement regulators improves complement-dependent effector functions of therapeutic anticancer antibodies targeting leukemic cells", ONCOIMMUNOLOGY, vol. 4, 2015, pages e979688
MELIS ET AL.: "Complement in therapy and disease: Regulating the complement system with antibody-based therapeutics", MOL IMMUNE, vol. 67, 2015, pages 117 - 130, XP029246895, DOI: doi:10.1016/j.molimm.2015.01.028
NORIS ET AL.: "Glomerular diseases dependent on complement activation, including atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, and C3 glomerulopathy: core curriculum 2015", AM J KIDNEY DIS, vol. 66, 2015, pages 359 - 375
PAN Z ET AL: "Development of activity-based probes for trypsin-family serine proteases", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 16, no. 11, 1 June 2006 (2006-06-01), pages 2882 - 2885, XP027965509, ISSN: 0960-894X, [retrieved on 20060601] *
PHILIPPE LESAVRE ET AL: "Inhibition of alternative pathway factor D by factor B -related synthetic hexapeptides", EUROPEAN JOURNAL OF IMMUNOLOGY, vol. 12, no. 3, 1 March 1982 (1982-03-01), pages 252 - 254, XP055158019, ISSN: 0014-2980, DOI: 10.1002/eji.1830120317 *
ROGERS ET AL.: "Complement in monoclonal antibody therapy of cancer", IMMUNOL RES, vol. 59, 2014, pages 203 - 210
WEBER ET AL.: "The role of the complement system in age-related macular degeneration", DTSCH ARZTEBL INT, vol. 111, 2014, pages 133 - 138
WONG ET AL.: "Complement therapy in atypical haemolytic uraemic syndrom (aHUS", MOL IMMUNOL, vol. 56, 2013, pages 199 - 212, XP028683633, DOI: doi:10.1016/j.molimm.2013.05.224

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