WO2016146730A1 - Peptides ayant une activité agoniste du récepteur trka ou une activité antagoniste du ngf - Google Patents

Peptides ayant une activité agoniste du récepteur trka ou une activité antagoniste du ngf Download PDF

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Publication number
WO2016146730A1
WO2016146730A1 PCT/EP2016/055777 EP2016055777W WO2016146730A1 WO 2016146730 A1 WO2016146730 A1 WO 2016146730A1 EP 2016055777 W EP2016055777 W EP 2016055777W WO 2016146730 A1 WO2016146730 A1 WO 2016146730A1
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ser
asp
phe
gly
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PCT/EP2016/055777
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Piercarlo Fantucci
Stefano Govoni
Emilio VANOLI
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Neuheart S.R.L.
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Publication of WO2016146730A1 publication Critical patent/WO2016146730A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/48—Nerve growth factor [NGF]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4711—Alzheimer's disease; Amyloid plaque core protein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to peptides and peptide fragments and their use.
  • the present invention relates to peptides and peptide fragments having TrkA-receptor-agonistic activity and their use for the treatment of conditions, diseases and disorders benefiting from an increased activation of the TrkA-receptor, in particular for the treatment of peripheral neuropathies, multiple sclerosis, Alzheimer's disease, Parkinson's disease, hypoxic brain injuries and optic nerve atrophy.
  • the present invention further relates to peptides and peptide fragments having NGF- antagonistic activity and their use for the treatment of conditions, diseases and disorders related to elevated levels of NGF, in particular for the treatment of pain and cardiac arrhythmias
  • the invention further relates to the use of the peptides and peptide fragments of the invention for the treatment of diseases characterised or aggravated by a loss of innervation such as ischemic heart disease, heart failure and diabetes and its comorbidities, in particular diabetic neuropathies.
  • the present invention relates to the use of the peptides and peptide fragments of the invention for the treatment of conditions, diseases and disorders shown to benefit from a treatment with NGF such as ulcers, neurotropic keratitis and glaucoma.
  • the invention further relates to the use of the peptides and peptide fragments of the invention for the treatment of diseases characterised or aggravated by a loss of innervation such as ischemic heart disease, heart failure and diabetes and its comorbidities, in particular diabetic neuropathies. Furthermore the present invention relates to the use of the peptides and peptide fragments of the invention for the treatment of conditions, diseases and disorders shown to benefit from a treatment with NGF such as ulcers, neurotropic keratitis and glaucoma.
  • Nerve growth factor is a protein that regulates the growth and survival of sympathetic and sensory nerve cells (neurons). NGF thereby belongs to a family of growth factors called neurotrophins. NGF binds to and activates its high affinity tyrosine kinase receptor TrkA. Upon activation the TrkA-receptor dimerises and autophosphorylates starting important signaling pathways for the growth and survival of sympathetic neurons.
  • NGF nerve growth factor
  • NGF neurotrophic factor
  • diseases and disorders include diabetic polyneuropathy, HIV-associated peripheral neuropathy, Alzheimer's disease, Parkinson's disease, optic glioma and advance optic nerve atrophy and hypoxic-ischemic perinatal brain injury (for a review of studies on the clinical use of NGF see Aloe et al, J. Transl Med. (2012) 10: 239).
  • NGF might be suitable for the treatment of other diseases and disorders such as ulcer, neurotropic keratitis and glaucoma (y.s.).
  • NGF neurotrophic factor
  • Pain and Johnson have become a target in the search for new pain management strategies.
  • One approach thereby employs NGF sequestration using anti-NGF antibodies such as Tanezumab (Pfizer), Fulranumab (Johnson and Johnson), REGN475/SAR164877 (Regeneron together with Sanofi Aventis) or medi578 (AstraZeneca).
  • anti-NGF antibodies such as Tanezumab (Pfizer), Fulranumab (Johnson and Johnson), REGN475/SAR164877 (Regeneron together with Sanofi Aventis) or medi578 (AstraZeneca).
  • Tanezumab is effective in reducing pain in both patient groups compared to placebo.
  • the invention relates to peptides and peptide fragments having an amino acid sequence selected from the group consisting of,
  • Peptides and peptide fragments of the invention are the peptides and peptide fragments having an amino acid sequence listed above and their salts, their solvates and the solvates of their salts as well as peptides and peptide fragments mentioned below as exemplary embodiments and the salts, solvates and solvates of the salts thereof, insofar as the peptide and peptide fragments mentioned below are not already salts, solvates or solvates of the salts.
  • Salts preferred for the purpose of the invention are physiologically acceptable salts of the peptides and peptide fragments of the invention. Also included however are salts which themselves are not suitable for pharmaceutical applications but can be used for example for the isolation or purification of the peptides and peptide fragments of the invention.
  • Solvates for the purpose of the invention refer to those forms of the peptides and peptide fragments of the invention which in the solid or liquid state form a complex by complexation with one or more solvent molecules. Hydrates are a specific form of solvates in which the complexation takes place with water.
  • peptide fragment in the context of the invention refers to peptides in which the amino acid sequences of the invention are incorporated into a larger peptide molecule. This can happen via a chain-extension at the C-terminus, the N-terminus or both termini.
  • the larger peptide molecule is not longer than 50 amino acids in total including the amino acid sequences of the invention. More preferably the larger peptide molecule is not longer than 35 amino acids including the amino acid sequences of the invention. In some embodiments it may be preferred if the amino acid sequences of the invention are extended by no more than 5 amino acids at either terminus.
  • the peptide or peptide fragments of the invention may have an amino acid sequence that does not comprise further amino acids added to either terminus. In any case the amino acid sequences of the invention will always be present in the sequences listed above and not interrupted by other amino acids.
  • an amino acid includes proteinogenic amino acids but also non-proteinogenic amino acids, such as D-amino acids or amino acids in which the amino group and the carbonyl group are not bonded to the same carbon but separated by at least one further carbon (e.g. ⁇ - or ⁇ -amino acids). If an amino acid is mentioned only by name this includes both L- and D-amino acids as well as ⁇ -, ⁇ - and higher order amino acids. In some embodiments a-amino acids may be preferred. In some embodiments L-amino acids may be preferred. In some embodiments a-L-amino acids may be preferred.
  • the peptides or peptide fragments of the invention may consist exclusively of L-amino acids or exclusively of D-amino acids. In some embodiments the peptides and peptide fragments of the invention consist of a mixture of L- and D-amino acids. In some embodiments the peptides and peptide fragments of the invention may contain at least one L-amino acid. In some embodiments the peptides and peptide fragments of the invention may contain at least one D-amino acid. In the context of the invention the names and abbreviations used have the usual meaning known to a person skilled in the art.
  • the present invention also relates to peptides or peptide fragments having an amino acid sequence selected from the group consisting of
  • the peptides and peptide fragments of the invention have an amino acid sequence selected from the group consisting of
  • peptides and peptide fragments of the invention have an amino acid sequence selected from
  • the peptides and peptide fragments of the invention show a valuable range of pharmaceutical properties that could not have been predicted.
  • the peptides and peptide fragments of the invention are in particular distinguished by their capability to bind to and activate the TrkA-receptor. They are therefore useful as in the treatment of diseases and disorders benefiting from an increased activation of the TrkA-receptor.
  • the peptides and peptide fragments of the invention are useful for the treatment of peripheral neuropathies, multiple sclerosis, Alzheimer's disease, Parkinson's disease, hypoxic brain injuries and/or optic nerve atrophy.
  • the peptides and peptide fragments of the invention are furthermore useful in the treatment of diseases and disorders characterised or aggravated by a loss of innervation such as ischemic heart disease, heart failure and diabetes and its comorbidities, in particular diabetic neuropathies.
  • the peptides and peptide fragments of the invention are also useful in the treatment of other diseases and disorders that have been shown to benefit from a treatment with NGF such as ulcers, neurotropic keratitis and/or glaucoma.
  • the peptides and peptide fragments of the invention are in particular distinguished by their capability to bind to the TrkA receptor more strongly than NGF without activating this receptor. They are therefore useful as NGF-antagonists in the treatment of diseases and disorders associated with an increase in the NGF-level.
  • the peptides and peptide fragments are useful in the treatment and management of pain and in the treatment and prophylaxis of hyperinnervation and conditions associated therewith such as cardiac arrhythmia and sudden cardiac death.
  • the present invention therefore also relates to the peptides and peptide fragments of the invention for use as medicaments.
  • the present invention further relates to the peptides and peptide fragments of the invention for use in the treatment, prophylaxis and/or management of diseases or disorders, in particular diseases or disorders benefiting from an increased activation of the TrkA-receptor, in particular for use in the treatment, prophylaxis and/or management of peripheral neuropathies, multiple sclerosis, Alzheimer's disease, Parkinson's disease, hypoxic brain injuries and/or optic nerve atrophy.
  • the present invention further relates to the peptides and peptide fragments of the invention for use in the treatment, prophylaxis and/or management of diseases or disorders characterised or aggravated by a loss of innervation, in particular for use in the treatment, prophylaxis and/or management of ischemic heart disease, heart failure and diabetes and its comorbidities, in particular diabetic neuropathies.
  • the present invention further relates to the peptides and peptide fragments of the invention for use in the treatment, prophylaxis and/or management of other diseases and disorders that have been shown to benefit from a treatment with NGF, in particular for use in the treatment, prophylaxis and/or management of ulcers, neurotropic keratitis and/or glaucoma.
  • the present invention further relates to the peptides and peptide fragments of the invention for use in the treatment, prophylaxis and/or management of diseases or disorders, in particular diseases or disorders related to NGF, more particularly diseases or disorders related to an elevated level of NGF.
  • the present invention further relates to the peptides and peptide fragments of the invention for use in the treatment and/or management of pain.
  • the present invention further relates to the peptides and peptide fragments of the invention for use in the treatment and/or prophylaxis of hyperinnervation.
  • the present invention further relates to the peptides and peptide fragments of the invention for use in the treatment and/or prophylaxis of cardiac arrhythmias and/or sudden cardiac death.
  • the peptides and peptide fragments of the present invention bind to the TrkA receptor and activate it, therefore acting as TrkA-receptor-agonists.
  • the peptides and peptide fragments of the invention are useful in the prophylaxis, treatment and management of diseases and disorders benefiting from an increased activation of the TrkA-receptor.
  • the peptides and peptide fragments of the invention are suitable to treat, prevent and/or manage peripheral neuropathies, multiple sclerosis, Alzheimer's disease, Parkinson's disease, hypoxic brain injuries and/or optic nerve atrophy.
  • peptides and peptide fragments of the invention are useful for the treatment, prophylaxis and/or management of diseases or disorders characterised or aggravated by a loss of innervation such as ischemic heart disease, heart failure and diabetes and its comorbidities, in particular diabetic neuropathies.
  • peptides and peptide fragments of the invention are useful for the treatment, prophylaxis and/or management of other diseases and disorders that have been shown to benefit from a treatment with NGF, such as ulcers, neurotropic keratitis and/or glaucoma.
  • the peptides and peptide fragments of the invention can also be used in the treatment and prophylaxis of the above conditions in animals such as primates, pigs, ruminants (cows, sheep, goats), horses, cats, dogs, poultry (e.g. chickens, ducks, geese, quails, pigeons, turkeys or ornamental birds) as well as productive and ornamental fish, reptiles and amphibians.
  • the present invention therefore further relates to a method for the prophylaxis, treatment and/or management of diseases or disorders benefiting from an increased activation of the TrkA- receptor in humans and animals comprising administering a therapeutically effective amount of the peptides or peptide fragments of the invention.
  • the present invention further relates to a method for treating, preventing and/or managing peripheral neuropathies, multiple sclerosis, Alzheimer's disease, Parkinson's disease, hypoxic brain injuries and/or optic nerve atrophy in humans and animals comprising administering a therapeutically effective amount of the peptides or peptide fragments of the invention.
  • the present invention further relates to a method for treating, preventing and/or managing diseases or disorders characterised or aggravated by a loss of innervation in humans and animals comprising administering a therapeutically effective amount of the peptides or peptide fragments of the invention.
  • the present invention further relates to a method for treating, preventing and/or managing ischemic heart disease, heart failure and diabetes and its comorbidities, in particular diabetic neuropathies in humans and animals comprising administering a therapeutically effective amount of the peptides or peptide fragments of the invention.
  • the present invention further relates to a method for treating, preventing and/or managing other diseases and disorders that have been shown to benefit from a treatment with NGF in humans and animals comprising administering a therapeutically effective amount of the peptides or peptide fragments of the invention.
  • the present invention further relates to a method for treating, preventing and/or managing ulcers, neurotropic keratitis and/or glaucoma in humans and animals comprising administering a therapeutically effective amount of the peptides or peptide fragments of the invention.
  • the peptides and peptide fragments of the invention may act systemically and/or locally.
  • they can be administered in a suitable way, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, bucally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
  • the peptides and peptide fragments of the invention can be administered in suitable administration forms.
  • Suitable for oral application are application forms which work according to the prior art and release the peptides and peptide fragments of the invention quickly or in a modified fashion, for example as a sustained release formulation.
  • These application forms may contain the peptides and peptide fragments of the invention in crystalline and/or amorphised and/or dissolved form.
  • Examples for such application forms include tablets (uncoated tablets or tablets having coatings such as enteric coatings or coatings that modify the release of the peptides and peptide fragments of the invention such as slowly dissolving coatings or insoluble coatings), tablets or films/wafers that disintegrate rapidly in the oral cavity, capsules (for example hard or soft gelatin capsules), films/lyophylisates, granules, pellets powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can take place with avoidance of an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with the inclusion of an absorption step (e.g. intramuscular, subcutaneous, percutaneous or intraperitoneal).
  • Administration forms for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Suitable for other administration routes are, for example, pharmaceutical forms for inhalation (inter alia powder inhalers or nebulisers) nasal drops, nasal solutions or nasal sprays; tablets, films/wafers or capsules for lingual, sublingual or buccal administration, suppositories, preparations for eyes and ears, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as for example patches), milks, pastes, foams, implants or stents.
  • pharmaceutical forms for inhalation inter alia powder inhalers or nebulisers
  • nasal drops nasal solutions or nasal sprays
  • tablets films/wafers or capsules for lingual, sublingual or buccal administration
  • suppositories preparations for eyes and ears
  • vaginal capsules vaginal capsules
  • aqueous suspensions such as for example patches
  • lipophilic suspensions ointments
  • creams such as for
  • peptides and peptide fragments of the invention can be incorporated into the listed administration forms. This can take place in ways that are know per se by mixing with inert, nontoxic, pharmaceutically suitable excipients.
  • pharmaceutically suitable excipients include for example carriers (e.g. microcrystalline cellulose, lactose or mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants and wetting agents (e.g. sodium dodecyl sulfate, polyoxysobitane oleate), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilisers (e.g. antioxidants such as ascorbic acid), colours (e.g. inorganic pigments such as iron oxides) and smell and/or taste masking agents.
  • carriers e.g. microcrystalline cellulose, lactose or mannitol
  • solvents e.g. liquid polyethylene glyco
  • peptides and peptide fragments of the invention in administration forms that modulate their pharmacokinetics and increase their transport through the blood brain barrier.
  • administration forms can be provided by absorbing or incorporating the peptides and peptide fragments of the invention onto/into nanoparticulate carriers.
  • Carriers that modulate the pharmacokinetics and increase the transport through the blood brain barrier include carriers made from biodegradable polymers such as biodegradable poly(alkyl cyanoacrylates), polyesters, polyanhydrides, polyethers or mixtures or copolymers thereof.
  • nano-scale carriers include carriers made from poly(butyl cyanoacrylate), polylactic acid, poly(lactic-co-glycolic acid), chitosan, polyethylene glycol or mixtures or copolymers thereof.
  • the nanoparticulate carriers are surface treated, for example coated with further compounds to promote the transport through the blood brain barrier.
  • Such further compounds for surface treating the nanoparticulate carriers include surfactants, polyethers, biological molecules and mixtures thereof.
  • the invention further relates to medicaments comprising at least one peptide or peptide fragment of the invention usually together with at least one inert, non-toxic, pharmaceutically acceptable excipient and their use for the above mentioned purposes.
  • medicaments comprising at least one peptide or peptide fragment of the invention usually together with at least one inert, non-toxic, pharmaceutically acceptable excipient and their use for the above mentioned purposes.
  • the peptides and peptide fragments of the present invention bind to the TrkA receptor and block it, therefore acting as an NGF antagonist.
  • the peptides and peptide fragments of the invention are useful in the prophylaxis, treatment and management of diseases and disorders related to an elevated level of NGF.
  • the peptides and peptide fragments of the invention are suitable to treat and/or manage pain, in particular chronic pain such as osteoarthritic pain, rheumatoid arthritis, chronic lower back pain, interstitial cystitis, prostatitis, chronic pelvic pain syndrome, fibromyalgia, endometriosis, degenerative intervertebral disc disease and cancer pain.
  • the peptides and peptide fragments of the invention are useful for the treatment and/or prophylaxis of hyperinnervation and conditions related thereto such as cardiac arrhythmias and sudden cardiac death.
  • the peptides and peptide fragments of the invention can also be used in the treatment and prophylaxis of NGF related conditions in animals such as primates, pigs, ruminants (cows, sheep, goats), horses, cats, dogs, poultry (e.g. chickens, ducks, geese, quails, pigeons, turkeys or ornamental birds) as well as productive and ornamental fish, reptiles and amphibians.
  • animals such as primates, pigs, ruminants (cows, sheep, goats), horses, cats, dogs, poultry (e.g. chickens, ducks, geese, quails, pigeons, turkeys or ornamental birds) as well as productive and ornamental fish, reptiles and amphibians.
  • the present invention therefore further relates to a method for the prophylaxis, treatment and/or management of diseases or disorders related to NGF, in particular elevated levels of NGF in humans and animals comprising administering a therapeutically effective amount of the peptides or peptide fragments of the invention.
  • the present invention further relates to a method for treating and/or managing pain in humans and animals comprising administering a therapeutically effective amount of the peptides or peptide fragments of the invention.
  • the present invention further relates to a method for treating and/or preventing hyperinnervation in humans and animals comprising administering a therapeutically effective amount of the peptides or peptide fragments of the invention.
  • the present invention further relates to a method for treating and/or preventing cardiac arrhythmias and/or sudden cardiac death in humans and animals comprising administering a therapeutically effective amount of the peptides or peptide fragments of the invention.
  • the expression managing pain or management of pain relates to all treatment regimes that will not completely rid the patient of the pain but will reduce the pain to improve or significantly improve the patient's quality of life.
  • the peptides and peptide fragments of the invention may act systemically and/or locally.
  • they can be administered in a suitable way, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, bucally, rectally, dermally, transdermally, conjunct! vally, otically or as an implant or stent.
  • the peptides and peptide fragments of the invention can be administered in suitable administration forms.
  • Suitable for oral application are application forms which work according to the prior art and release the peptides and peptide fragments of the invention quickly or in a modified fashion, for example as a sustained release formulation.
  • These application forms may contain the peptides and peptide fragments of the invention in crystalline and/or amoiphised and/or dissolved form.
  • Examples for such application forms include tablets (uncoated tablets or tablets having coatings such as enteric coatings or coatings that modify the release of the peptides and peptide fragments of the invention such as slowly dissolving coatings or insoluble coatings), tablets or films/wafers that disintegrate rapidly in the oral cavity, capsules (for example hard or soft gelatin capsules), films/lyophylisates, granules, pellets powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can take place with avoidance of an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with the inclusion of an absorption step (e.g. intramuscular, subcutaneous, percutaneous or intraperitoneal).
  • Administration forms for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Suitable for other administration routes are, for example, pharmaceutical forms for inhalation (inter alia powder inhalers or nebulisers) nasal drops, nasal solutions or nasal sprays; tablets, films/wafers or capsules for lingual, sublingual or buccal administration, suppositories, preparations for eyes and ears, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as for example patches), milks, pastes, foams, implants or stents.
  • pharmaceutical forms for inhalation inter alia powder inhalers or nebulisers
  • nasal drops nasal solutions or nasal sprays
  • tablets films/wafers or capsules for lingual, sublingual or buccal administration
  • suppositories preparations for eyes and ears
  • vaginal capsules vaginal capsules
  • aqueous suspensions such as for example patches
  • lipophilic suspensions ointments
  • creams such as for
  • peptides and peptide fragments of the invention can be incorporated into the listed administration forms. This can take place in ways that are know per se by mixing with inert, nontoxic, pharmaceutically suitable excipients.
  • pharmaceutically suitable excipients include for example carriers (e.g. microcrystalline cellulose, lactose or mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants and wetting agents (e.g. sodium dodecyl sulfate, polyoxysobitane oleate), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilisers (e.g.
  • compositions such as ascorbic acid
  • colours e.g. inorganic pigments such as iron oxides
  • smell and/or taste masking agents e.g. inorganic pigments such as iron oxides
  • Such administration forms can be provided by absorbing or incorporating the peptides and peptide fragments of the invention onto/into nanoparticulate carriers.
  • Carriers that modulate the pharmacokinetics and increase the transport through the blood brain barrier include carriers made from biodegradable polymers such as biodegradable poly(alkyl cyanoacrylates), polyesters, polyanhydrides, polyethers or mixtures or copolymers thereof.
  • examples of potentially useful nano-scale carriers include carriers made from poly(butyl cyanoacrylate), polylactic acid, poly(lactic-co-glycolic acid), chitosan, polyethylene glycol or
  • the nanoparticulate carriers are surface treated, for example coated with further compounds to promote the transport through the blood brain barrier.
  • Such further compounds for surface treating the nanoparticulate carriers include surfactants, polyethers, biological molecules and mixtures thereof.
  • the invention further relates to medicaments comprising at least one peptide or peptide fragment of the invention usually together with at least one inert, non-toxic, pharmaceutically acceptable excipient and their use for the above mentioned purposes.
  • peptides and peptides fragments of the invention may be combined with other pharmaceutically active compounds, for example other analgesics or compounds useful in the treatment of cardiac arrhythmias and sudden cardiac death such as for example beta-blockers.
  • other pharmaceutically active compounds for example other analgesics or compounds useful in the treatment of cardiac arrhythmias and sudden cardiac death such as for example beta-blockers.
  • Analgesics suitable for use in combination with the peptides and peptides fragments of the invention include for example non-steroidal anti-inflammatories such as paracetamol, ibuprofen, aspirin, diclofenac or naproxen, COX-2 inhibitors such as rofexocib, celecoxib and etoricoxib and opioids such as codeine, oxycodone, hydrocodone, dihydromorphine or pethidine, as well as other know analgesics.
  • non-steroidal anti-inflammatories such as paracetamol, ibuprofen, aspirin, diclofenac or naproxen
  • COX-2 inhibitors such as rofexocib, celecoxib and etoricoxib
  • opioids such as codeine, oxycodone, hydrocodone, dihydromorphine or pethidine, as well as other know analgesics.
  • Beta-blockers suitable for use in combination with the peptides and peptides fragments of the invention include for example acebutolol, atenolol, betaproxol, bisoprolol, bucindolol, butaxamine, carteolol, carvedilol, celiprolol, esmolol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol and timolol.
  • the invention further relates to medicaments comprising at least one peptide or peptide fragment having TrkA agonistic activity or NGF-antagonistic activity according to the invention usually together with at least one further pharmaceutically active ingredient and their use for the above mentioned purposes.
  • the minimum amount of the peptides and peptide fragments of the invention to be administered is a therapeutic amount.
  • therapeutically effective amount means an amount of compound which prevents the onset of, alleviates the symptoms of, manages, stops the progression and/or eliminates a disease, disorder or condition benefiting from an increased activation of the TrkA-receptor, a disease, disorder or condition characterized or aggravated by a loss of innervation or another disease, disorder or condition shown to benefit from a treatment with NGF.
  • an effective dosing scheme of the peptides and peptide fragments of the invention in adults is about 1 to 1000 ⁇ g kg of the peptides or peptide fragments of the invention, preferably 5 to 500 ⁇ g kg.
  • the effective dose is 5 to 100 ⁇ ]3 ⁇ 4 or 10 to 50 ⁇ g/kg. In other embodiments the effective dose is 1 to 20 g/kg or 2 to 10 ⁇ g/kg.
  • the peptides and peptide fragments of the invention are administered daily. In some embodiments the peptides or peptide fragments of the invention are administered every other day or every 3, 5, 7 or 10 days. In some cases it might be necessary to titrate the patient to find the optimal dose.
  • CHB and fun are compensatory functions for the non-ideality of the specific bond and are expressed as a sum over all hydrogen-bond sites;
  • ADj is a term for the atomic desolvation describing variations in the solvation field of ligand atoms.
  • TrkA and NGF form a unique complex from two NGF and two TrkA molecules each, forming two homo-dimers.
  • the present inventors have mapped the short contact distances between the two TrkA molecules and the two NGF molecules in order to find the smallest representative TrkA-NGF complex. This investigation has shown that the highest number of short range interactions occur between the first molecule of the NGF and second molecule of TrkA. Specific distances between the closest a-carbon atoms in the first NGF molecule and the second TrkA molecule are given below in Table 1. Table 1 Distances between the a-carbon atoms of NGF(l) and TrkA(2)
  • the above peptides can be prepared by conventional solid state synthesis.
  • the synthesis proceeds along the well known cycle of coupling step, washing step, removal of the protecting group and washing step after which another coupling step follows or if the peptide is complete the peptide is cleaved from the solid support.
  • a polystyrene resin can be used as support.
  • the amino functionality of the amino acid can for example be protected using a tert,- butyloxycarbonyl (Boc) protecting group.
  • Boc tert,- butyloxycarbonyl
  • Other suitable protecting groups can be used for any present reactive side-chain functionality.
  • the Boc protecting group can be replaced by a 9-fluorenylmethyloxycarbonyl (Fmoc) protecting group.
  • the coupling reaction proceeds using coupling agents usual in the art, such as a combination of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) or N,N'-dicyclohexylcarbodiimide
  • EDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • DCC 1-hydroxy-benzotriazole
  • HOBt 1-hydroxy-benzotriazole
  • TMP tetramethylpiperidine
  • Suitable solvents for the coupling reaction include dimethyl formamide (DMF), N-methylpyrrolidone (NMP), trichloromethane (TCM) and dichloromethane (DCM) or mixtures thereof. Additionally further solvents such as trifluorethanol (TFE), hexafluoro-2-propanol (HFIP) or dimethylsulfoxide (DMSO) may be added to suppress peptide aggregation.
  • TFE trifluorethanol
  • HFIP hexafluoro-2-propanol
  • DMSO dimethylsulfoxide
  • the washing steps in general use solvents similar to those of the coupling steps.
  • the removal of the protecting groups proceeds using suitable deprotecting agents.
  • the Boc protecting group is usually removed under acidic conditions using for example hydrochloric acid (HQ) or trifluoroacetic acid (TFA), where appropriate in a suitable solvent such as for example methanol or ethanol for HC1 and for example DCM or TCM for TFA.
  • the Fmoc protecting group is usually removed in the presence of a base, such as for example pyridine, where appropriate in a suitable solvent.
  • the peptide After the peptide is complete it can be cleaved from the solid support in a suitable manner and purified as necessary. The whole process can be performed on an automated synthesizer.
  • the ability of the peptides and peptide fragments of the invention to act as a TrkA-receptor- agonist can for example be measured using an enzyme-linked immunosorbent assay (ELISA) for the phosphorylated TrKA-receptor.
  • ELISA enzyme-linked immunosorbent assay
  • Such an ELISA kit is commercially available for example from Cell Signalling Technologies under the designation PathScan® Phospho-TrkA (Tyr674/675) Sandwich ELISA Kit (catalogue number 7212).
  • the assay is used according to the manufacturers instructions exposing PC 12 or other cellular types expressing TrkA receptors to the peptides and peptide fragments of the invention. The measurements can be calibrated against various NGF concentrations.
  • the ability of the peptides and peptide fragments of the invention to act as a TrkA-receptor- agonist can also be measured using a ⁇ -NGF-induced neurite regeneration bioassay.
  • the assay used is based on the methodology described by Chandler et al. (J. Biol. Chem. (1984) 259, No. 1 1, 6882-6889).
  • PC 12 cells are grown on tissue culture plates (e.g. 60-mm Falcon ⁇ cell culture dishes) at an initial cell density of 4-5 x 10 5 cells/plate. During the cultivation ⁇ -NGF is added every other day for 8 days. The cells are harvested mechanically using a pasteur pipet, washed once in serum- containing growth medium and twice in serum-free growth medium and collected by centrifugation (500 g for 3 min. each time). The cell are resuspended at 6 x 10 3 cells/ml in serum-free growth medium and 0.5 ml each were plated into each well of a 24-well tissue culture plate.
  • tissue culture plates e.g. 60-mm Falcon ⁇ cell culture dishes
  • the tissue culture plate was pre-treated with 50 ⁇ g/ml poly-L-lysine (Sigma Aldrich) and washed four times with sterile distilled water.
  • the cells are incubated at 37° C for 30 min and 400 ⁇ Dulbecco's modified Eagle's medium containing bovine serum albumin (BSA) are added to bring the final serum albumin concentration to 1 mg/ml.
  • BSA bovine serum albumin
  • the cells are returned to the incubator for 15 min before 10 pm of ⁇ -NGF or various concentrations of the peptides of the invention (e.g. 0, 1 , 2, 5, 10, 20 pm) are added. At least one set of cells is used as control without the addition of ⁇ -NGF.
  • the cells are incubated for 24h at 37° C and read-out using a phase contrast microscope. Positives are cells which show a neurite growth of at least more than 25 ⁇ ⁇ ⁇ .
  • the TrkA-receptor-agonistic activity of the peptides of the invention is evaluated based on their ability to stimulate neurite growth compared to NGF-induced positive cells.
  • the ability of the peptides and peptide fragments of the invention to treat, manage or prevent diseases or disorders benefiting from an increased activation of the TrkA-receptor or other diseases and disorders that have been shown to benefit from a treatment with NGF can be shown in suitable animal models.
  • the ability of the peptides of the invention to treat or prevent Alzheimer's disease can for example be demonstrated in a rat model using the Morris water maze.
  • the Morris water maze can generally provide information on the activity of the tested compounds on memory, a target of potential interest for aging and dementing diseases, further conditions that might benefit from an increased TrkA-receptor agonism.
  • the ability of the peptides of the invention to treat diabetic ulcers can for example be demonstrated in a mouse model. Diabetes can be induced in mice using streptozotocin. Diabetic mice are then wounded using e.g. a biopsy punch and treated topically with the peptides and peptide fragments in a suitable solvent, e.g. saline solution. The wound closure is then observed visually or using digital imaging and compared to control animals treated with placebo, e.g. just the suitable solvent without the addition of the peptides or peptide fragments of the invention. D.
  • Example for a pharmaceutical composition e.g. a pharmaceutical composition
  • DMSO l% DMSO/99% Plasma
  • the peptide is completely dissolved in a calculated volume of DMSO.
  • the DMSO solution is then suspended in plasma and the suspension is mixed until a clear solution is obtained.
  • the solution is sterilized by filtration and dispensed into suitable containers.
  • Eflex accounts for the loss of flexibility of the ligand
  • Cm and f s are compensatory functions for the non-ideality of the specific bond and are expressed as a sum over all hydrogen-bond sites;
  • AD is a term for the atomic desolvation describing variations in the solvation field of ligand atoms.
  • TrkA and NGF form a unique complex from two NGF and two TrkA molecules each, forming two homo-dimers.
  • the present inventors have mapped the short contact distances between the two TrkA molecules and the two NGF molecules in order to find the smallest representative TrkA-NGF complex. This investigation has shown that the highest number of short range interactions occur between the first molecule of the NGF and second molecule of TrkA. Specific distances between the closest a-carbon atoms in the first NGF molecule and the second TrkA molecule are given below in Table 1.
  • the free binding energy of the starting peptide to TrkA was calculated as -13.02 Kcal/mol. Based on this the present inventors have investigated various mutated forms of the starting peptide showing one, two or three mutations. They have then selected those peptides which showed an improvement of at least -4 kcal/mol in the free binding energy compared to the starting peptide for further investigation. This improved in free binding energy shows an increased ability of the peptide to bind to TrkA and displace NGF. Due to the small size of the peptides they lack the ability to dimerise or to induce the dimerization in TrkA. Consequently these peptides cannot activate TrkA. Due to their improved free binding energy these peptides will furthermore displace NGF and consequently act as an NGF antagonist. The improvements in free binding energy of the mutated peptides are given below in Table 2.
  • the above peptides can be prepared by conventional solid state synthesis.
  • the synthesis proceeds along the well known cycle of coupling step, washing step, removal of the protecting group and washing step after which another coupling step follows or if the peptide is complete the peptide is cleaved from the solid support.
  • a polystyrene resin can be used as support.
  • the amino functionality of the amino acid can for example be protected using a tert.- butyloxycarbonyl (Boc) protecting group.
  • Boc tert.- butyloxycarbonyl
  • Other suitable protecting groups can be used for any present reactive side-chain functionality.
  • the Boc protecting group can be replaced by a 9-fluorenylmethyloxycarbonyl (Fmoc) protecting group.
  • the coupling reaction proceeds using coupling agents usual in the art, such as a combination of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) or N,N'-dicyclohexylcarbodiimide (DCC) with 1 -hydroxy -benzotriazole (HOBt) and l-hydroxy-7-aza-benzotriazole (HO At), where appropriate in the presence of a base, in particular a hindered base such as diisoproplethylamine (DIE A) or tetramethylpiperidine (TMP).
  • DIE A diisoproplethylamine
  • TMP tetramethylpiperidine
  • Suitable solvents for the coupling reaction include dimethylforniamide (DMF), N-methylpyrrolidone (NMP), trichloromethane (TCM) and dichloromethane (DCM) or mixtures thereof. Additionally further solvents such as trifluorethanol (TFE), hexafluoro-2-propanol (FIFIP) or dimethylsulfoxide (DMSO) might be added to suppress peptide aggregation.
  • DMF dimethylforniamide
  • NMP N-methylpyrrolidone
  • TCM trichloromethane
  • DCM dichloromethane
  • TFE trifluorethanol
  • FIFIP hexafluoro-2-propanol
  • DMSO dimethylsulfoxide
  • the washing steps in general use solvents similar to those of the coupling steps.
  • the removal of the protecting groups proceeds using suitable deprotecting agents.
  • the Boc protecting group is usually removed under acidic conditions using for example hydrochloric acid (HCl) or trifluoroacetic acid (TFA), where appropriate in a suitable solvent such as for example methanol or ethanol for HCl and for example DCM or TCM for TFA.
  • HCl hydrochloric acid
  • TCM trifluoroacetic acid
  • a suitable solvent such as for example methanol or ethanol for HCl and for example DCM or TCM for TFA.
  • the ability of the peptides and peptide fragments of the invention to act as an NGF antagonist can for example be measured using an enzyme-linked immunosorbent assay (ELISA) for the phosphorylated TrKA-receptor.
  • ELISA enzyme-linked immunosorbent assay
  • Such an ELISA kit is commercially available for example from Cell Signalling Technologies under the designation PathScan® Phospho-TrkA (Tyr674/675) Sandwich ELISA Kit (catalogue number 7212).
  • the assay is used according to the manufacturers instructions exposing PC 12 or other cellular types expressing TrkA receptors to a given amount of NGF added per well in combination with various quantities of the peptides and peptide fragments of the invention.
  • the activity of the peptides and peptide fragments is evaluated based on their ability to suppress the NGF induced autophosphorylation of TrkA and consequently the appearance of phospho-TrkA.
  • the ability of the peptides and peptide fragments of the invention to act as an NGF antagonist can also be measured using a ⁇ -NGF-induced neurite regeneration bioassay.
  • the assay used is based on the methodology described by Chandler et al. (J. Biol. Chem. (1984) 259, No. 11, 6882-6889).
  • PC 12 cells are grown on tissue culture plates (e.g. 60-mm Falcon ⁇ cell culture dishes) at an initial cell density of 4-5 x 10 5 cells/plate. During the cultivation ⁇ -NGF is added every other day for 8 days. The cells are harvested mechanically using a pasteur pipet, washed once in serum- containing growth medium and twice in serum-free growth medium and collected by 3
  • the cell are resuspended at 6 x 10 cells/ml in serum-free growth medium and 0.5 ml each were plated into each well of a 24-well tissue culture plate.
  • the tissue culture plate was pre-treated with 50 ⁇ g/ml poly-L-lysine (Sigma Aldrich) and washed four times with sterile distilled water.
  • the cells are incubated at 37° C for 30 min and 400 ⁇ Dulbecco's modified Eagle's medium containing bovine serum albumin (BSA) are added to bring the final serum albumin concentration to 1 mg/ml.
  • BSA bovine serum albumin
  • the cells are returned to the incubator for 15 min before 10 pm of ⁇ -NGF and various concentrations of the peptides of the invention (e.g. 0, 1, 2, 5, 10, 20 pm) are added. At least one set of cells is used as control without the addition of ⁇ -NGF.
  • the cells are incubated for 24h at 37° C and read-out using a phase contrast microscope. Positives are cells which show a neurite growth of at least more than 25 ⁇ .
  • the NGF-antagonistic activity of the peptides of the invention is evaluated based on their ability to reduce the number of NGF-induced positive cells.
  • the ability of the peptides of the invention to treat or manage pain can be demonstrated in a mouse or rat model.
  • Arthritis can be induced by the injection of bovine type II collagen into the joints of a test animal. After the arthritis has established the animals are treated once or several times with different doses of the peptides and peptide fragments of the invention.
  • the ability of the peptides and peptide fragments of the invention to treat pain can be observed through the restoration of mobility in arthritic animals.
  • DMSO l% DMSO/99% Plasma
  • the peptide is completely dissolved in a calculated volume of DMSO.
  • the DMSO solution is then suspended in plasma and the suspension is mixed until a clear solution is obtained.
  • the solution is sterilized by filtration and dispensed into suitable containers.

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Abstract

L'invention concerne de nouveaux peptides et fragments peptidiques et leur utilisation. En particulier, la présente invention concerne des peptides et des fragments peptidiques ayant une activité agoniste du récepteur TrkA utilisés pour traiter, prévenir ou prendre en charge les maladies ou les troubles tels que les neuropathies périphériques, la sclérose en plaques, la maladie d'Alzheimer, la maladie de Parkinson, les lésions cérébrales hypoxiques, les cardiopathies ischémiques, l'insuffisance cardiaque, le diabète et ses comorbidités, l'atrophie du nerf optique, les ulcères, la kératite neurotrophique et/ou le glaucome. L'invention porte en outre sur des peptides et des fragments peptidiques ayant une activité antagoniste du TrkA utilisés pour traiter, prévenir ou prendre en charge les maladies ou les troubles tels que la douleur, l'hyper-innervation, l'arythmie cardiaque et la mort subite d'origine cardiaque.
PCT/EP2016/055777 2015-03-19 2016-03-17 Peptides ayant une activité agoniste du récepteur trka ou une activité antagoniste du ngf WO2016146730A1 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
US10618974B2 (en) 2018-02-28 2020-04-14 Eli Lilly And Company Anti-TrkA antibody

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WO2005019266A2 (fr) * 2003-07-15 2005-03-03 Amgen Inc. Anticorps neutralisants anti-ngf humains utilises comme inhibiteurs selectifs de la voie de ngf
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WO2005025514A2 (fr) * 2003-09-10 2005-03-24 King's College London Composes qui modulent la croissance neuronale et leurs utilisations

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BERRERA MARCO ET AL: "MOLECULAR SIMULATION OF THE BINDING OF NERVE GROWTH FACTOR PEPTIDE MIMICS TO THE RECEPTOR TYROSINE KINASE A", BIOPHYSICAL JOURNAL, CELL PRESS, US, vol. 91, no. 6, 15 September 2006 (2006-09-15), pages 2063 - 2071, XP009084087, ISSN: 0006-3495, DOI: 10.1529/BIOPHYSJ.106.083519 *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10618974B2 (en) 2018-02-28 2020-04-14 Eli Lilly And Company Anti-TrkA antibody

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