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WO2011141891A1 - Utilisation de composés cycloundécadepsipeptides - Google Patents

Utilisation de composés cycloundécadepsipeptides Download PDF

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Publication number
WO2011141891A1
WO2011141891A1 PCT/IB2011/052096 IB2011052096W WO2011141891A1 WO 2011141891 A1 WO2011141891 A1 WO 2011141891A1 IB 2011052096 W IB2011052096 W IB 2011052096W WO 2011141891 A1 WO2011141891 A1 WO 2011141891A1
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axx
meleu
leu
meala
mebmt
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Grégoire VUAGNIAUX
Bruno Gavillet
Rafael CRABBÉ
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Debio Recherche Pharmaceutique SA
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Debio Recherche Pharmaceutique SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to cycloundecadepsipeptide compounds and analogues presenting mitochondrial permeability transition pore (MPTP) inhibitory activity and reduced cytotoxicity.
  • the present invention further relates to the pharmaceutical compositions containing cycloundecadepsipeptide compounds and analogues for use in the treatment and/or prevention of cell death associated disorders and diseases, related to the MPTP opening.
  • MPTP mitochondrial permeability transition pore
  • Oxidative stress accompanied by calcium overload, ATP depletion, and elevated phosphate levels induces mitochondrial permeability transition (MPT) with formation of nonspecific MPT pores (MPTP) in the inner mitochondrial membrane.
  • MPT mitochondrial permeability transition
  • MPTP nonspecific MPT pores
  • MPT results from opening of mitochondrial permeability transition pores (MPT pores or MPTP) (Halestrap 2010).
  • MPT induction is a key event in cell death and is implicated in a variety of disorders and diseases. For example:
  • MPT also appears to play a key role in damage caused by ischemia, as occurs in a heart attack and stroke (Baines, Kaiser et al. 2005; Nakagawa, Shimizu et al. 2005; Schinzel, Takeuchi et al. 2005; Halestrap 2010). • Research has shown that the MPT pore remains closed during ischemia, but opens once the tissues are reperfused with blood after the ischemic period, playing a role in reperfusion injury (Lim, Hausenloy et al. 2010).
  • MPT is also thought to underlie the cell death induced by Reye's syndrome, since chemicals that can cause the syndrome, like salicylate and valproate, cause
  • MPT may also play a role in mitochondrial autophagy (Lemasters, Nieminen et al. 1998).
  • Neurodegeneration a process that results in damage and death of neurons, is also a disorder where MPTP is found to be involved (Barrientos, Martinez et al. ; Du and Yan ; Du, Guo et al. 2008; Ibarra and Martinon 2009; Martin, Gertz et al. 2009).
  • MPTP plays an important role in muscular dystrophies (Palma, E., T. Tiepolo, et al. 2009; Millay, D. P., M. A. Sargent, et al. 2008
  • MPTP is involved in cell death induced by metabolic stress and/or oxidative stress and/or loss of cellular calcium homeostasis and/or aging cells and/or toxic agents (pathogens) and/or infectious agents (pathogens) (Burke et al. 2007; King et al. 2008; Sokol et al. 2005; Plotnikov et al. 2009).
  • MPTP is accepted as a therapeutic target for both pharmacological and conditional strategies to block pore formation by direct interaction with MPTP components or indirectly by decreasing MPTP inducers (Zorov, Juhaszova et al. 2009; Giorgio, Soriano et al. 2010).
  • sanglifehrin A as well as attenuation of reactive oxygen species accumulation through mitochondria-targeted antioxidants, is the most promising.
  • Inhibiting the opening of the MPTP can treat and/or prevent cell death associated disorders and diseases.
  • the MPTP opening has an important role in triggering organ dysfunction and pathology.
  • Cell death associated disorders and diseases, wherein the MPTP opening is involved include but are not limited to, ischaemia-reperfusion injuries, metabolic and/or oxidative stress disorders, diseases involving loss of cellular calcium homeostasis, age related cellular degeneration, diseases involving toxic and/or infectious pathogens.
  • Ischaemia and ischaemia-reperfusion injury the opening of the MPTP may be induced by ischaemia-reperfusion and can play an important role in the following diseases or conditions:
  • cell death associated diseases or disorders relate to the MPTP opening, involve organ dysfunction or pathologies in which the opening of the MPTP may be also an important trigger for cell death and is induced by metabolic stress and/or oxidative stress and/or loss of cellular calcium homeostasis and/or aging cells and/or toxic agents (pathogens) and/or infectious agents (pathogens) including but not limited to:
  • muscular dysthrophies including but not limited to Ulrich congenital
  • ⁇ neurodegenerative diseases including but not limited to: amyothrophic lateral sclerosis (ALS) (Martin, Gertz et al. 2009; Martin 2010), Alzheimer disease (Du and Yan 2010), Parkinson disease , multiple sclerosis (Forte, Gold et al. 2007), Huntington disease (Brustovetsky, Houseovetsky et al. 2003)
  • Agents that block MPT include the immune suppressant cyclosporin A (CsA) N-methyl-Val-4-cyclosporin A (MeVal-4-CsA), a non-immunosuppressant derivative of CsA; another non-immunosuppressive agent, NIM81 1 , 2- aminoethoxydiphenyl borate (2-APB), and bongkrekic acid.
  • CsA immune suppressant cyclosporin A
  • MeVal-4-CsA N-methyl-Val-4-cyclosporin A
  • NIM81 1 another non-immunosuppressive agent
  • 2-APB 2- aminoethoxydiphenyl borate
  • bongkrekic acid bongkrekic acid.
  • DEBIOPHARM SA relates to the use of a cyclic undecapeptide for the preparation of a medicament for administration during a myocardial ischaemic event.
  • WO 2009/098533 (DEBIOPHARM SA) relates to the use of a non-immunosuppressive cyclosporin A derivative for preventing or reducing muscular degeneration in a subject suffering from Limb- Girdle muscular Dystrophy.
  • Naturally occurring cyclosporins and derivatives present MPTP inhibitory activity but simultaneously display cytotoxicity which limits their anti-cell death effect.
  • the aim of the present invention is to provide new series of compounds with reduced cytotoxicity resulting in enhanced anti-cell death activity.
  • the present invention provides a cydoundecadepsipeptide compound of Formula (I) Cyclo-(AXXi-AXX 2 -AXX3-AXX 4 -AXX5-AXX6-AXX 7 -D-Hiv-MeLeu-Leu-lvleVal) (I)
  • AXXi is MeBmt, 4-fluoro-MeBmt, dihydro-MeBmt, 8-hydroxy-MeBmt;
  • AXX 2 is Abu, Val, Thr, Thr(OMe), Thr(OAc), Thr(OCOCH 2 CH 2 CH 2 OH), Nva, 5-hydroxy-Nva (Hnv);
  • AXX 3 is D-MeAla, D-3-fluoro-MeAla, D-MeSer, D-MeSer(OAc),
  • AXX 4 is Melle, MeMet, MeVal, MeThr, MeThr(OAc), MeAla, EtVal, Etlle, EtPhe, EtTyr, EtThr(OAc), MeThr(OAc), MeTyr, MeTyr(OAc), MeTyr(OMe), MePhe, MeMet(Ox) wherein the sulphur atom of methionine is sulphoxyde or sulphone;
  • AXX 5 is Leu, Val, lie, Gly, Abu;
  • AXX 6 is MeAla, Sar, MeLeu;
  • AXX 7 is Gly, Ala; for use in a method for treating and/or preventing cell death associated disorders and diseases, related to the MPTP opening,
  • the present invention further provides the use of a pharmaceutical composition for treating and/or preventing cell death associated disorders and diseases, related to the MPTP opening, comprising a compound of the invention, together with one or more pharmaceutically acceptable diluents or carriers.
  • the term “comprise” is generally used in the sense of include, that is to say permitting the presence of one or more features or components.
  • Treatment refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder or the disease as well as those in which the disorder is to be prevented. Hence, the mammal to be treated herein may have been diagnosed as having the disorder or the disease may be predisposed or susceptible to the disorder or the disease.
  • “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals or pet animals, such as dogs, horses, cats, cows, monkeys etc. Preferably, the mammal is human.
  • the term "therapeutically effective amount” refers to an amount of a drug effective to treat a disease or disorder in a mammal.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • cell death associated disorders and diseases comprises disorders and diseases caused by, associated with, linked with, mediated by or accompanied by the MPTP opening or wherein the MPTP opening is involved.
  • Cell death encompasses the normal degeneration and death of living cells, also defined as the terminal failure of a cell to maintain essential life functions, or the point in the process of dying at which vital functions have ceased at the cellular level.
  • Cell death includes for example apoptosis as well as necrosis often defined as the morphological changes indicative of cell death caused by progressive enzymatic degradation; it may affect groups of cells or part of a structure or an organ.
  • a "disorder” refers to an underlying pathological disturbance in a symptomatic or asymptomatic organism relative to a normal organism, which may result, for example, from infection, stress or an acquired or congenital genetic imperfection.
  • the invention refers to a series of cycloundecadepsipeptide compounds, with or without immunosuppressant activity, presenting mitochondrial permeability transition pore (MPTP) inhibitory activity and reduced cytotoxicity.
  • MPTP mitochondrial permeability transition pore
  • AXXi is MeBmt, 4-fluoro-MeBmt, dihydro-MeBmt, 8-hydroxy-MeBmt;
  • AXX 2 is Abu, Val, Thr, Thr(OMe), Thr(OAc), Thr(OCOCH 2 CH 2 CH 2 OH), Nva, 5-hydroxy-Nva;
  • AXX 3 is D-MeAla, D-3-fluoro-MeAla, D-MeSer, D-MeSer(OAc),
  • AXX 4 is Melle, MeMet, MeVal, MeThr, MeThr(OAc), MeAla, EtVal, Etlle, EtPhe,
  • EtTyr EtThr(OAc), MeThr(OAc), MeTyr, MeTyr(OAc), MeTyr(OMe), MePhe, MeMet(Ox) wherein the sulphur atom of methionine is sulphoxyde or sulphone;
  • AXX 5 is Leu, Val, lie, Gly, Abu;
  • AXX 6 is MeAla, Sar, MeLeu;
  • AXX 7 is Gly, Ala; for use in a method for treating and/or preventing cell death associated disorders and diseases, related to the MPTP opening, and wherein said
  • cycloundecadepsipeptide compound of Formula (I) comply with the two following criteria: (1 ) MPTP inhibitory activity at least equal to half of the CsA activity, defined as:
  • said cycloundecadepsipeptide compound of Formula (I) is at least 5 fold less cytotoxic than CsA, and even more preferably at least ten-fold less cytotoxic than CsA, defined as:
  • CsA _ cell _ count _ IC 50 Calcium retention capacity is a sensitive measure of the propensity of mitochondria to open the Permeability Transition Pore (MPTP) after Ca 2+ uptake.
  • the IC2 (nM) is the concentration of compound necessary to double the CRC, relative to the CRC observed in the absence of any compound (CRCo).
  • cyclodepsipeptides are natural or synthetic compounds having sequences of amino and hydroxyl carboxylic acid residues (usually a-amino and a-hydroxy acids) and the residues are connected in a ring (see lUPAC Compendium of Chemical Terminology, 2 nd Edition (1997). Such cyclodepsipeptides are depicted as heterodetic peptides in which at least one amide bond has been replaced with an ester bond.
  • the compounds of the present invention comprise eleven residues, ten being a- amino acids and one being ⁇ -hydroxy acid. This ⁇ -hydroxy acid is
  • (2R)-2-hydroxy-3-methyl-butanoic acid also known as D-a-hydroxyisovaleric acid and abbreviated as H-D-Hiv-OH.
  • this hydroxyl acid is in position 8. It forms on the carboxylic acid end an amide bond with the amino group of the ⁇ -amino acid in position 9, namely N-methyl-leucine, and, on the hydroxyl end an ester bond with the carboxylic acid group of the a-amino acid in position 7, namely alanine or glycine.
  • the a-amino acids of Formula (I) are mentioned using the three letter code abbreviation usually used to name amino acids and their configuration is
  • An advantage of the compounds according to the present invention may lie in the impact of an ester bond within macro cyclic backbone in comparison to the regular cyclic amide backbone of the corresponding cycloundecapeptide compounds described in the prior art. Without being bound to theory, it is believed that the replacement of an amide by an ester bond between amino-acid AXX 7 in position 7 and D-HIV in position 8 results in a strong effect upon the conformational and physico-chemical properties such as increased conformational flexibility and lipophilicity as well as the absence of a hydrogen donor bond.
  • the new class of compounds also offers an improved preparation process, especially at an industrial scale.
  • the invention also encompasses chemical modifications of the compounds of formula I to prolong their circulating lifetimes.
  • suitable poly(ethylene glycol) derivatives that possess this property are described in e.g. US 2005171328 (NEKTAR THERAPEUTICS AL CORP) or US 6,713,454 (NOBEX CORP).
  • the compounds of the present invention are defined by
  • AXXi is MeBmt
  • AXX 2 is Abu. Val
  • AXX 3 is D-MeAla
  • AXX 4 is Melle, MeVal, EtVal;
  • AXX 5 is Leu, Val, lie, Gly, Abu;
  • AXX 6 is MeAla, Sar, MeLeu;
  • AXX 7 is Gly, Ala.
  • compounds of Formula (I) are selected among:
  • CsA cyclosporine A
  • the compounds of the present invention have reduced cytotoxicity, which allows (1 ) possible use of higher doses to achieve a maximal effect; (2) increased therapeutic window and (3) no lack of activity at high doses.
  • MPTP opening is a key event in the biochemical signaling that underlies mitochondria mediated cell death in various tissues, disorders and diseases.
  • the cell death associated disorders and diseases are selected from the group comprising ischaemia-reperfusion injuries, metabolic and/or oxidative stress disorders, diseases involving loss of cellular calcium homeostasis, age related cellular degeneration, diseases involving toxic and/or infectious pathogens.
  • the cell death associated disorders and diseases, related to the MPTP opening are selected from the group comprising ischaemia and ischaemia- reperfusion injuries, muscular dysthrophies, neurodegeneration disorders and diseases, West Nile viral encephalitis, Japanese encephalitis, Chronic hepatitis and cirrhosis induced by Hepatitis C virus, Hepatitis B, delta agent, acute and chronic drug- or toxin-induced hepatotoxicity, alcoholic liver disease, cholestasis, Non Alcoholic Fatty Liver Disease, gastro-intestinal ulcerations caused by
  • NSAIDs transplant rejection, peripheral vascular insufficiency, renal insufficiency, obesity, diabetic micro-angiopathy, diabetic nephropathy, Maturity onset diabetes of the young type 4, acute and chronic pancreatitis, septicaemia, multi organ dysfunction syndrome, crush syndrome, congestive heart failure, atherosclerosis, hypertensive heart disease, cancer, bipolar disorder.
  • Ischaemia and ischaemia-reperfusion injuries are selected from the group comprising acute cerebral ischemia, acute stroke, acute myocardial infarction cardiac arrest, myocardial stunning, post-reperfusion arrhythmias, organ failure following therapeutic procedures such as thrombolytic therapy, coronary angioplasty, aortic cross-clamping or coronary bypass surgery, hypovolemic shock, storage/reperfusion injury of transplant organs, multi organ dysfunction syndrome.
  • Muscular dysthrophies are selected from the group comprising Ulrich congenital muscular dysthrophy, Bethlem myopathy, myosclerosis, limb girdle muscular dysthropy, Duchenne muscular dysthrophy, Becker muscular
  • Neurodegeneration disorders and diseases are selected from the group comprising traumatic brain injury, spinal cord injury, peripheral nerve injury, epilepsy-induced brain injury, amyothrophic lateral sclerosis (ALS), Alzheimer disease, Parkinson disease , multiple sclerosis, Huntington disease, axonal degeneration-induced neuropathic pain, diabetic neuropathy chemotherapy- induced neuropathic pain, or herpes-induced neuropathy.
  • the cell death associated disorders and diseases, related to the MPTP opening are selected among acute and chronic pancreatitis and muscular dystrophy Pancreatitis is an inflammation of the pancreas that can occur in two very different forms.
  • Acute pancreatitis is sudden while chronic pancreatitis is characterized by recurring or persistent abdominal pain with or without steatorrhea or diabetes mellitus.
  • Acute pancreatitis is a severe and frequently lethal disorder most commonly caused by gallstone disease and alcohol abuse, whereas chronic pancreatitis is a long-standing inflammation of the pancreas that alters its normal structure and functions.
  • Acute pancreatitis is characterized by acinar cell necrosis which contributes to pancreatic and extra-pancreatic autodigestion as well as systemic inflammatory response and multiple organ failure.
  • a key event in acinar cell necrosis is the formation of the MPTP within the inner mitochondrial membrane leading to permeabilization of the mitochondrial membrane.
  • the compounds have the ability to prevent acinar cell necrosis and attenuate the pancreatic injury.
  • Muscular dystrophies comprise a diverse group of genetic disorders that lead to muscle wasting and, in many instances, premature death. It was demonstrated (Millay et al., 2008) that mitochondrial-dependent necrosis represents a prominent disease mechanism in muscular dystrophy. Indeed one major mechanism leading to cellular necrosis is mitochondrial calcium overload, which secondarily enhances reactive oxygen species (ROS) generation and further promotes MPT
  • ROS reactive oxygen species
  • the compounds of the present invention may be obtained by applying classical peptide (solution or solid-phase peptide synthesis; in Houben - Weyl, Methods of Organic Chemistry, Vol. E 22d, Ed. -in-Chief: M. Goodman, Thieme Verlag, Stuttgart, 2003) and organic chemistry or biotechnology, for instance by applying the chemical tools as described by Wenger in Helv. Chim. Acta, 67, 502-25, 1984 or in Helv. Chim. Acta, 66, 2672-702 (1983) and by employing HATU as coupling reagent described in Rich, D.H. et al.. Comparative studies of the coupling of N- methylated, sterically hindered amino acids during SPPS, Tetr. Letters. 35, 5981 - 5984 (1994).
  • Fragment (Ax) may be as follows:
  • Fragment A which contains the a-hydroxy acid residue D-Hiv, may be obtained by degradation of a natural cydoundecadepsipeptide (namely Cyclo-(MeBmt-Thr-Sar- MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal), the preparation of said cydoundecadepsipeptide being described either in US 5,1 16,816, Example 2, or in WO 02/092033, Example 4, Step 4-1 .
  • a natural cydoundecadepsipeptide namely Cyclo-(MeBmt-Thr-Sar- MeLeu-Leu-MeLeu-Ala-D-Hiv-MeLeu-Leu-MeVal
  • ALISPORIVIR [D-MeAla] 3 -[EtVal] 4 -CsA as described in WO 2006/038088, DEBIOPHARM SA).
  • the synthesis of the expensive dipeptide derivative Boc-D-MeAla-EtVal-OH (including 4 chemical steps) is not needed.
  • some of the compounds contain a C-terminal Glycine, which facilitates the last step of the synthesis (macrolactonisation, no epimerisation).
  • the costs for reagents and starting compounds are considerably lower in case of the compounds according to the invention.
  • the "reagent of Meerwein" used for the ring opening reaction of CsA is not needed.
  • Fragment B (hexapeptide AXX 2 -AXX 7 ) can be efficiently obtained by standard solid-phase peptide synthesis using commercially starting compounds.
  • the overall yield for obtaining the pharmacologically interesting compounds can amount up to 80%.
  • the present invention further provides a pharmaceutical composition for treating and/or preventing cell death associated disorders or diseases, related to the MPTP opening, comprising a compound of the invention, together with one or more pharmaceutically acceptable diluents or carriers.
  • the compounds of the present invention may be administrated for instance parenterally or orally to a patient in need, for instance incorporated in a pre- concentrated microemultion.
  • the compounds of the present invention, their pharmaceutically acceptable salts and pro-drugs thereof, where applicable, may be administered in the form of a pharmaceutical composition in which they are in association with a
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • the compounds of the present invention may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano- particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano- particles and nanocapsules
  • Sustained-release preparations may be prepared. Suitable examples of sustained- release preparations include semi permeable matrices of solid hydrophobic polymers containing the compounds of the present invention, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained- release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl- methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No.
  • compositions of the invention may be formulated as creams, gels, solutions, ointments, suspensions or plasters etc. when intended for topical administration; for administration by inhalation, e.g. as aerosols or dry powders; for oral administration, e.g. in the form of tablets, capsules, gels, syrups, suspensions, solutions, powders or granules; for rectal or vaginal administration e.g. as suppositories; or for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular, intrathecal or infusion) as a sterile solution, suspension or emulsion.
  • parenteral injection including intravenous, subcutaneous, intramuscular, intravascular, intrathecal or infusion
  • the active compound of the invention may be administered by any conventional route. It may be administered parentally, e.g., in the form of injectable solutions or suspensions, or in the form of injectable deposit formulations. Preferably, it will be administered orally in the form of solutions or suspensions for drinking, tablets or capsules.
  • the pharmaceutical compositions of the invention typically comprise a cycloundecadepsipeptide compound of the invention and one or more
  • compositions for parenteral administration typically also include one or more excipients.
  • excipients include an isotonic agent, a buffer or other pH- controlling agent, and a preservative. These excipients may be added for maintenance of the composition and for the
  • the indicated dosage of a cycloundecadepsipeptide compound of the invention for daily to trice weekly administration may be from about 1 mg/kg to about 100 mg/kg, preferably from about 1 mg/kg to about 20 mg/kg.
  • the indicated corresponding dosage may be from about 1 mg/kg to about 50 mg/kg, preferably from about 1 mg/kg to about 25 mg/kg.
  • An effective amount of a cydoundecadepsipeptide compound of the invention is understood to be an amount that when administered in the course of a therapeutic regimen to a patient in need of treatment of MPTP opening mediated disorder results in an objective clinical response.
  • cydoundecadepsipeptide compound of the invention Additional factors include the weight of the patient, the age of the patient, and the general condition of the patient. A course of treatment will require repeated administration of a
  • composition of the invention Typically, an adequate drug dose will be administered in one single administration (i.e. a unique dose) or repeatedly for example 3-7 times per week, and the duration of treatment may be for example from about 4 weeks to 6 months, preferably from about 4 weeks to about 12 months.
  • a pharmaceutical composition of the present invention may comprise one or more other active ingredients which present MPTP inhibitory activity in addition to the compounds of the present invention. Compounds of the invention and such other active ingredients can be administered together as part of the same
  • the appropriate dose regimen, the amount of each dose administered, and specific intervals between doses of each active agent will depend upon the specific combination of active agents employed, the condition of the patient being treated, and other factors discussed in the previous section. Such additional active ingredients will generally be administered in amounts less than or equal to those for which they are effective as single therapeutic agents.
  • the FDA approved dosages for such active agents that have received FDA approval for administration to humans are publicly available.
  • the compounds of the invention may be administered as the sole ingredient or together with other drugs.
  • AXXi is MeBmt, 4-fluoro-MeBmt, dihydro-MeBmt, 8-hydroxy-MeBmt;
  • AXX 2 is Abu, Val, Thr, Thr(OMe), Thr(OAc), Thr(OCOCH 2 CH 2 CH 2 OH), Nva, 5-hydroxy-Nva;
  • AXX 3 is D-MeAla, D-3-fluoro-MeAla, D-MeSer, D-MeSer(OAc),
  • AXX 4 is Melle, MeMet, MeVal, MeThr, MeThr(OAc), MeAla, EtVal, Etlle, EtPhe, EtTyr, EtThr(OAc), MeThr(OAc), MeTyr, MeTyr(OAc), MeTyr(OMe), MePhe, MeMet(Ox) wherein the sulphur atom of methionine is sulphoxyde or sulphone;
  • AXX 5 is Leu, Val, lie, Gly, Abu;
  • AXX 6 is MeAla, Sar, MeLeu;
  • AXX 7 is Gly, Ala; and wherein said cycloundecadepsipeptide compound of Formula (I) comply with the two following criteria:
  • said cycloundecadepsipeptide compound of Formula (I) is at least 5 fold less cytotoxic than CsA, and even more preferably at least ten-fold less cytotoxic than CsA, defined as:
  • the cell death associated disorders and diseases, wherein the MPTP opening is involved are selected from the group comprising ischaemia-reperfusion injuries, metabolic and/or oxidative stress disorders, diseases involving loss of cellular calcium homeostasis, age related cellular degeneration, diseases involving toxic and/or infectious pathogens.
  • the cell death associated disorders and diseases, related to the MPTP opening are selected from the group comprising ischaemia and ischaemia- reperfusion injuries, muscular dysthrophies, neurodegeneration disorders and diseases, West Nile viral encephalitis, Japanese encephalitis, Chronic hepatitis and cirrhosis induced by Hepatitis C virus, Hepatitis B, delta agent, acute and chronic drug- or toxin-induced hepatotoxicity, alcoholic liver disease, cholestasis, Non Alcoholic Fatty Liver Disease, gastro-intestinal ulcerations caused by
  • NSAIDs transplant rejection, peripheral vascular insufficiency, renal insufficiency, obesity, diabetic micro-angiopathy, diabetic nephropathy, Maturity onset diabetes of the young type 4, acute and chronic pancreatitis, septicaemia, multi organ dysfunction syndrome, crush syndrome, congestive heart failure, atherosclerosis, hypertensive heart disease, cancer, bipolar disorder.
  • Ischaemia and ischaemia-reperfusion injuries are selected from the group comprising acute cerebral ischemia, acute stroke, acute myocardial infarction cardiac arrest, myocardial stunning, post-reperfusion arrhythmias, organ failure following therapeutic procedures such as thrombolytic therapy, coronary angioplasty, aortic cross-clamping or coronary bypass surgery, hypovolemic shock, storage/reperfusion injury of transplant organs, multi organ dysfunction syndrome.
  • Muscular dysthrophies are selected from the group comprising Ulrich congenital muscular dysthrophy, Bethlem myopathy, myosclerosis, limb girdle muscular dysthropy, Duchenne muscular dysthrophy, Becker muscular
  • Neurodegeneration disorders and diseases are selected from the group comprising traumatic brain injury, spinal cord injury, peripheral nerve injury, epilepsy-induced brain injury, amyothrophic lateral sclerosis (ALS), Alzheimer disease, Parkinson disease , multiple sclerosis, Huntington disease, axonal degeneration-induced neuropathic pain, diabetic neuropathy chemotherapy- induced neuropathic pain, or herpes-induced neuropathy.
  • traumatic brain injury spinal cord injury, peripheral nerve injury
  • epilepsy-induced brain injury amyothrophic lateral sclerosis (ALS), Alzheimer disease, Parkinson disease , multiple sclerosis, Huntington disease, axonal degeneration-induced neuropathic pain, diabetic neuropathy chemotherapy- induced neuropathic pain, or herpes-induced neuropathy.
  • ALS amyothrophic lateral sclerosis
  • Alzheimer disease Parkinson disease
  • multiple sclerosis Huntington disease
  • axonal degeneration-induced neuropathic pain diabetic neuropathy chemotherapy- induced neuropathic pain
  • the cell death associated disorders and diseases, related to the MPTP opening are selected among acute and chronic pancreatitis and muscular dystrophy
  • Another object of the invention is a method, comprising co-administration concomitantly or in sequence of a therapeutically effective amount of the compound according to the invention or the pharmaceutical composition of the invention and a co-agent selected from an agent having blocking properties on MPTP opening.
  • a pharmaceutical combination of the invention results in a beneficial effect, e. g. a synergistic therapeutic effect, compared to a monotherapy applying only one of its pharmaceutical active ingredients.
  • a synergistic combination is for example a combination of the
  • reaction mixture was diluted with DCM (60 mL) and washed with H 2 O (1 x 1 0 mL) and brine (1 x 1 0 mL).
  • the organic phase was filtered, dried (Na 2 SO 4 ), evaporated and dried under high vacuum.
  • the crude amine salt of H-MeLeu-Ala-OMe was used for the next coupling step without further purification.
  • Boc-D-MeAla-EtVal-OH was obtained starting from Boc-D-MeAla-Val-OMe using BuLi and Triethyloxoniumfluoroborate, followed by hydrolysis of the methylester according to literature [Jean Frangois. Guichou, PhD thesis entitled “De technical analogues de Cyclosporine A comme agent anti-VIH-1 ", Faculte des Sciences, Universite de Lausanne, 2001 , p.1 21 -1 22] . 2.6. Preparation of Boc-D-MeAla-EtVal-Leu-MeLeu-Ala-OMe
  • the crude mixture was separated by CC to give the pentapeptide Boc-D-MeAla-EtVal-Leu-MeLeu-Ala-OMe as an oil.
  • the sample was repurified by semi-preparative RP-HPLC and the product was lyophilized to give the
  • D-MeAla-EtVal-Leu-MeLeu-Ala-OMe was used to the next coupling step without further purification.
  • a sample of crude product (23 mg) was re-purified by semi- preparative RP-HPLC and the peptide was lyophilized to give Fragment (Ba) H-Abu-D-MeAla-EtVal-Leu-MeLeu-Ala-OMe as a white powder.
  • the MPTP activity was evaluated by measuring the Calcium Retention Capacity (CRC) of mouse liver mitochondrial preparations.
  • CRC Calcium Retention Capacity
  • MPC Permeability Transition Pore
  • CRC of mitochondria was assessed fluorimetrically using the Ca2+ indicator Calcium Green-5N. Mitochondria was incubated 1 min with ranging concentrations of the test compound and the concentration of compound necessary to double the CRC (IC 2 ) was determined by constructing dose-response curves.
  • Mitochondria were isolated from the liver of 9-10 week old male C57BI/6j mice. After isolation the liver was kept at 4°C in a Tris-buffered (pH 7.4) sucrose-based isotonic solution and quickly minced and homogenized with a Teflon/glass potter. The suspension was spun for 6 min at 700 x g, and the resulting supernatant was spun for 6 min at 7,000 x g. The mitochondrial pellet was carefully resuspended in excess volume of sucrose buffer and spun again as above. The final mitochondrial pellet was resuspended with a minimal volume of sucrose buffer. Protein concentration was determined with the biuret method. Mitochondrial suspensions were used immediately and not beyond 4 h from isolation.
  • the CRC of mitochondrial preparations was assessed fluorimetrically in the presence of the Ca 2+ indicator Calcium Green-5N at room temperature using a Fluoroskan Ascent FL fluorometer (Thermo Electron Corporation).
  • Every treatment was represented by the mean value ⁇ SD of (1 ) the CRC and (2) the ratio between CRC (as just defined) and CRCo (concentration of Ca 2+ which opens the PTP in the absence of the compound).
  • IC2 (nM) was calculated as the concentration of compound necessary to double the CRC, relative to the CRC observed in the absence of any compound (CRCo).
  • Cytotoxicity was evaluated by measuring proliferation of HepG2 cells. Cells were incubated with ranging concentrations of the test compound for 72hrs. Cell proliferation is measured by the signal intensity of the incorporated nuclear dye. The half maximal inhibitory concentration (IC 5 0) was determined by constructing dose-response curves.
  • Cells were grown in RPMI 1640, 10%FBS, 2 mM L-alanyl-L-Glutamine, 1 mM Na Pyruvate or a special medium in a humidified atmosphere of 5% CO2 at 37°C. Cells were seeded into 384-well plates and incubated in a humidified atmosphere of 5% CO2 at 37°C. Compounds were added 24 hours post cell seeding. At the same time, a time zero untreated cell plate was generated.
  • IC 5 o is the test compound concentration that produces 50% of the cell proliferation inhibitory response or 50% cytotoxicity level.
  • AIM MathlQ based software
  • Table 1 shows that the selected compounds according to the invention have a MPTP inhibitory activity at least equal to half of the CsA activity as well as at least equal to half of the activity of the compounds of the prior art.
  • the selected compounds of the invention are at least three-fold less cytotoxic than CsA as well as least three-fold less cytotoxic than the compounds of the prior art.
  • Example 3 Acute pancreatitis Models The compounds have been shown to significantly ameliorate disease outcome in the bile acid-induced murine acute pancreatitis model which closely reproduce clinical pathologies.
  • the bile acid-induced murine acute pancreatitis model is similar to gallstone induced clinical acute pancreatitis, which results from retrograde passage of bile into the pancreatic duct when gallstones impact at the sphincter of Oddi.
  • Gallstone pancreatitis is the commonest form of the disease within the majority of countries in the world, except those where alcohol consumption is relatively very high.
  • Biliary pancreatitis was induced by retrograde perfusion of the pancreatic duct with 2 mM TLCS; sacrifice and assessments were made 24 hours later (Laukkarinen, J.M. et al, 2007).
  • the bile acid-induced murine acute pancreatitis model is a close representative of clinical acute pancreatitis, underlining the possible clinical utility of an early administration of compound 057 as a treatment for this disease.
  • OATP1 B1 organic anion transporting polypeptide 1 B1
  • Hepatitis C virus protein expression causes calcium-mediated mitochondrial bioenergetic dysfunction and nitro-oxidative stress.”

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Abstract

La présente invention porte sur des analogues de composés cycloundécadepsipeptides présentant une activité d'inhibition des pores de transition de perméabilité mitochondriale (PTPm) et une cytotoxicité réduite. La présente invention porte en outre sur une composition pharmaceutique contenant un composé cycloundécadepsipeptide et des analogues destinée à être utilisée dans le traitement ou la prévention de troubles ou maladies associés à la mort cellulaire, liés à l'ouverture des PTPm.
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CN104768968A (zh) * 2012-10-02 2015-07-08 西普拉里斯有限公司 环状缩酚肽化合物及其用途

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US9382295B2 (en) 2012-10-02 2016-07-05 Cypralis Limited Cyclic depsipeptide compounds and their uses
US9895412B2 (en) 2012-10-02 2018-02-20 Cypralis Limited Cyclic depsipeptide compounds and their uses
CN104768968B (zh) * 2012-10-02 2019-04-05 西普拉里斯有限公司 环状缩酚肽化合物及其用途

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