WO2018068120A1 - Utilisation d'un composé, produit intermédiaire de synthèse, composition pharmaceutique et méthode thérapeutique de neuromodulation - Google Patents

Utilisation d'un composé, produit intermédiaire de synthèse, composition pharmaceutique et méthode thérapeutique de neuromodulation Download PDF

Info

Publication number
WO2018068120A1
WO2018068120A1 PCT/BR2017/050314 BR2017050314W WO2018068120A1 WO 2018068120 A1 WO2018068120 A1 WO 2018068120A1 BR 2017050314 W BR2017050314 W BR 2017050314W WO 2018068120 A1 WO2018068120 A1 WO 2018068120A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
hydrogen
pharmaceutical composition
nfkf
preparation
Prior art date
Application number
PCT/BR2017/050314
Other languages
English (en)
Portuguese (pt)
Inventor
Ricardo Amaral Remer
Andrea Sterman Heimann
Original Assignee
Proteimax Biotecnologia Ltda
Remer Consultores Assessoria Empresarial Ltda
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from BR102016023848-0A external-priority patent/BR102016023848A2/pt
Priority claimed from BR102017010169-0A external-priority patent/BR102017010169A2/pt
Application filed by Proteimax Biotecnologia Ltda, Remer Consultores Assessoria Empresarial Ltda filed Critical Proteimax Biotecnologia Ltda
Priority to IL273868A priority Critical patent/IL273868B1/en
Publication of WO2018068120A1 publication Critical patent/WO2018068120A1/fr
Priority to PCT/BR2018/050156 priority patent/WO2018209415A1/fr
Priority to BR112019002655A priority patent/BR112019002655A2/pt
Priority to JP2019564034A priority patent/JP7241032B2/ja
Priority to EP18802073.9A priority patent/EP3626727A4/fr
Priority to CN201880047283.1A priority patent/CN110891963B/zh
Priority to US16/612,220 priority patent/US20220098237A1/en

Links

Classifications

    • 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
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4

Definitions

  • the present invention is in the fields of pharmacy, medicine, chemistry and biotechnology. More specifically, the present invention describes a compound and its use for preparing a binder of diagnostic and / or therapeutic interest, a synthetic intermediate in the preparation of compounds of pharmaceutical interest, the use of a compound for preparing a cannabinoid receptor modulating medicament and / or muscarinic, a pharmaceutical composition containing said compound and a therapeutic method.
  • the pharmaceutical composition of the invention comprises a peptidic compound and is particularly useful for the modulation of metabolic function or neuromodulation and may be administered orally.
  • oral administration of the composition of the invention demonstrated significant and surprising results in the curative or prophylactic treatment of seizures.
  • Test results indicate that the compound of the invention interacts with and / or modulates the activity of cannabinoid (CB) receptors, especially CB1 and / or CB2, the pharmaceutical composition of the invention being a promising alternative to the administration of cannabinoid compounds currently known as anticonvulsants, such as cannabidiol.
  • CBD cannabinoid
  • the present invention describes a compound and its use for the preparation of pharmaceutical compositions useful for a varied set of medical conditions.
  • the pharmaceutical composition of the invention is useful under medical conditions related to the central nervous system.
  • the composition of the invention comprises a peptide active
  • oral administration has provided brain effects in animals.
  • in vivo tests with the composition of the invention demonstrated surprising results as to its neuromodulatory activity.
  • the pharmaceutical composition of the invention when administered previously to animals, provided surprising, potent and long protection against damage resulting from the subsequent administration of substances known to be harmful to neurons. Accordingly, neuromodulation or neuroprotection provided by the compound of the invention is particularly useful as a therapeutic alternative for various medical conditions, including those related to neuronal excitability disorders.
  • in vivo tests with the compound of the invention have shown surprising results regarding its anticonvulsant activity.
  • the compound of the invention when used as an anticonvulsant, additionally provides the advantage of being a good candidate to substitute the cannabinoid compounds known for their acting as anticonvulsants, such as Canabidiol.
  • Cannabidiol despite its proven effects as an anticonvulsant, has been facing regulatory problems due to its origin, the Cannabis sativa plant.
  • the present invention provides an additional therapeutic approach for patients suffering from seizures and having difficulty in obtaining drugs, being based on a peptide and not using Cannabis sativa derivatives.
  • the results showed that the compound of the invention, when used as an anticonvulsant, provides other surprising technical advantages in use, including greater therapeutic effect, oral use, lower dosage, less occurrence of side effects such as prostration and nasal bleeding, among others advantages.
  • Pilocarpine (commonly called "Pilo") is an alkaloid extracted from the leaves of the jaborandi plant (Pilocarpus jaborand ⁇ ), a plant used for centuries by the Tupi-Guarani Indians who inhabit Brazil and take advantage of their properties to produce sweat and saliva .
  • Pilocarpine is a non-specific muscarinic agonist, slowly degraded and has no effects on the nicotinic receptors and was introduced in clinical practice by the Brazilian physician Sifrônio Coutinho, in 1874, through extracts of the jaborand ⁇ leaf to obtain diaphoretic effect (sweat production) and silagogue (saliva production).
  • pilocarpine at high concentrations induces the occurrence of convulsions, being used as an experimental model for both.
  • Pilocarpine-induced seizures lead to neurotoxicity at the cellular level and may be related to increased cerebral oxidative stress and changes in the concentration of certain amino acids (Santos et al, 201 1).
  • pilocarpine causes cholinergic alterations capable of inducing status epilepticus (SE) associated with convulsive stereotyped movements.
  • SE status epilepticus
  • Pilo is able to induce epilepticus status both administered directly in the brain and intraperitoneally.
  • Acetylcholine through its muscarinic receptor (mAChRs) plays an important role in cognitive functions, such as learning and memory.
  • MAChRs are receptors that form G protein-receptor complexes on the cell membranes of certain neurons and other cells. They play several roles, including acting as the ultimate end receptor stimulated by acetylcholine released from postganglionic fibers in the parasympathetic nervous system.
  • Muscarinic receptors are so called because they are more sensitive to muscarin than to nicotine. Its counterparts are nicotinic acetylcholine receptors (nAChRs), channels of receptor ions that are also important in the autonomic nervous system. Many drugs and other substances (eg, pilocarpine and scopolamine) manipulate these two distinct receptors acting as selective agonists or antagonists.
  • nAChRs nicotinic acetylcholine receptors
  • Many drugs and other substances eg, pilocarpine and scopolamine
  • the mAChRs are among the most well characterized among the transmembrane receptors (7TM), being widely expressed in the central nervous system (CNS).
  • Seven mAChR subtypes were cloned (M1, M2, M3, M4 and M5) and are generally divided into two distinct classes based on signal transduction.
  • mAChR M1, M3 and M5 are subtypes that signal through Gq / 11 proteins and activate phospholipase-C and mobilize intracellular calcium.
  • M2 and M4 mAChR predominate through Gi / o proteins inhibiting adenylate cyclase and reducing the intracellular concentration of cAMP.
  • the predominant mAChR in the CNS is the M1 subtype, which is located in the cortex, hippocampus, striatum and thalamus, where it is found post-synaptic.
  • the M2 mAChRs are located predominantly in the brainstem and thalamus, but also in the cortex, hippocampus and striatum, where they control the release of acetylcholine.
  • the MAChRs of M3 and M5 are expressed at much lower levels than Mh or Mh MAChRs in the CNS, but Mh MAChRs are found in the cortex and hippocampus, while M5 mAChRs have a very discrete location in the substantia nigra.
  • MAChR M4 are found in many regions of the brain, including the cortex and hippocampus, but are more prominent in the striatum, where they are thought to play a role in the control of dopamine release and modulate locomotor activity.
  • test results presented in the present patent application indicate that the composition of the invention interacts with cannabinoid and / or muscarinic receptor receptors.
  • the results show that the compound of the invention modulates the action of neurons and is also neuroprotective and anticonvulsive.
  • CB cannabinoid
  • the cannabinoid system which comprises the CB1 and CB2 receptors and their endogenous ligands, acts on various metabolic functions, including control of food intake, energy and / or lipid metabolism, regulation of intestinal motility, immune system, in the balance of the calcium cycle, among others.
  • Cannabinoid receptors are widely expressed in the brain, including the cortex, hippocampus, amygdala, pituitary, and hypothalamus.
  • CB receptors, particularly CB1 have already been identified in numerous peripheral organs and tissues, including the thyroid gland, adrenal gland, reproductive organs, adipose tissue, liver, muscle, and gastrointestinal tract.
  • WO 2014/008567 discloses compounds and compositions useful for treating metabolic disorders comprising obesity, diabetes, systemic arterial hypertension (or disease, condition related and / or associated comorbidities); prevention of overweight; regulation of appetite; induction of satiety; prevention of weight gain after successful weight loss; increased energy consumption; aesthetic weight reduction; or bulimia.
  • No report or suggestion of use of the compound of the invention as neuromodulator, neuroprotective or as anticonvulsant is made in said document, because this approach was not imagined by the inventors nor was it obvious from the state of the art.
  • WO 201 01/01187 discloses the use of hemopressin for the treatment of obesity in a subject and further discloses that hemopressin is a compound that binds effectively to the CB1 receptor.
  • the present invention differs from said document, among other reasons, to provide a composition for other therapeutic uses, in addition to revealing other compounds with surprising activity.
  • the test results performed by the inventors have been surprising, especially in regard to neuromodulation, neuroprotection and inhibition of seizures, facts not described or suggested in said document.
  • WO 2013/021 196 discloses the use of hemopressin as an agent that interferes with oligodentine differentiation and is useful as an anti-demyelinating agent.
  • the present invention differs from said document, among other reasons, in that it provides other compounds, other uses and provides benefits when compared to hemopressin, including ease of preparation, improved stability and activity, among other advantages.
  • the test results performed by the inventors have been surprising, especially in regard to neuromodulation, neuroprotection and / or inhibition of the occurrence of seizures with the compounds of the invention, which are neither described nor suggested in said document.
  • MAIOROV V. N .
  • CRIPPEN G. M. Significance of root-mean-square deviation in comparing three-dimensional structures of globular proteins. Journal of Molecular Biology, v. 235, p. 625-634, 1994.
  • MORGAN C.A .
  • HURLEY T. D. Characterization of two distinct structural classes of selective aldehyde dehydrogenase 1 A1 inhibitors. Journal of Medicinal Chemistry, v. 58, p. 1964-1975, 2015.
  • PERTWEE, R. G. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: A9-tetrahydrocannabinol, cannabidiol and ⁇ 9-tetrahydrocannabivarin. British Journal of Pharmacology, v. 153, p. 199-215, 2008.
  • RAMACHANDRAN G. N .
  • RAMAKRISHNAN C
  • SASISEKHARAN V. Stereochemistry of polypeptide chain configurations. Journal of Molecular Biology, v. 7, p. 95-99, 1963.
  • the present invention addresses a number of known problems of the prior art, for example, to provide: a stable peptidic compound, a synthetic intermediate in the preparation of compounds of pharmaceutical interest, use of the compound to prepare a binder of interest and / or neuromodulatory modulatory pharmaceutical composition containing said compound; the use of a medicament for modulating the cannabinoid and / or muscarinic system; the use of the peptidic compound for the preparation of a medicament for the curative or prophylactic treatment of seizures; a molecular entity that provides these and / or other technical effects without the drawbacks arising from the use of the cannabinoid substances such as prostration and nasal bleeding, among others; a pharmaceutical composition useful as a therapeutic alternative for neuromodulation and / or for preventing or treating seizures; a therapeutic method.
  • AA is an amino acid selected from the group consisting of F, W, L, I, V, P, G; AA 2 is hydrogen or an amino acid selected from the group consisting of F, W, L, I, V, P, G;
  • R 1 is hydrogen, the amino acid V, or dipeptide PV
  • R 2 is absent when AA 2 is hydrogen or is hydrogen, the amino acid L, or the dipeptide LS when R 1 is hydrogen,
  • AA is F, W, or L.
  • Ri and R2 are both hydrogen.
  • Embodiments of the peptidic compound of the invention useful in the various objects thereof include one or more peptides selected from the group consisting of consists of: NFK, NWK, NLK, NWK, NLKF, NWKF, NWKF, NWKWL, NWKW, NLKW, NLKW, NWKL, NWKLL, NWKLL, NWKLL, NLKLL, , VNFKF, VNWKW, VNLKL, VNFKFL, VNWKWL, VNLKLL, PVNFKF, PVNWKW, PVNLKL, NFKFLS, NWKWLS, NLKLLS, as well as modified, cyclic, amidated, methylated, PEGylated forms thereof; their salts or combinations thereof.
  • the peptidic compound of the invention is selected from the group comprising tripeptide, NFK, NFKF tetrapeptide, NFKL tetrapeptide, or combinations thereof.
  • the compound of the invention provides improved stability and / or ease of handling, being particularly useful in pharmaceutical and drug preparations.
  • the compound of the invention also provides oral administration to a mammalian animal.
  • the compound of the invention provides advantages in the administration, bioavailability and / or therapeutic action in an animal when compared to other peptides, such as hemopressin and known variants, usually of larger size.
  • Another object of the present invention is a synthetic intermediate in the preparation of compounds of pharmaceutical interest which comprise the compound described above and may include chemical modifications, substitutions, inclusion of other functional groups.
  • Another object of the present invention is the use of the compound described above for the preparation of other compounds of pharmaceutical interest, said compounds comprising the compound described above and chemical modifications, substitutions, other functional groups.
  • Administration of the compound of the invention to a mammal provides neuromodulatory, neuroprotective and / or anticonvulsant activity; enables oral administration in animals; does not have or entails the drawbacks arising from the production, storage, transport and use of cannabinoid substances, in addition to providing additional advantages in the preparation of therapeutic products for mammals in their administration and / or effects.
  • administering provides important and surprising technical advantages, including superior anticonvulsant activity over hemopressin, the use of which as an anticonvulsant is the subject of the co-pending co-pending application of the same inventors.
  • Another object of the present invention is a therapeutic method for metabolic modulation and / or neuromodulation comprising administering to an animal the peptide described above.
  • Another object of the invention is a neuromodulatory, neuroprotective pharmaceutical composition and / or for the curative or prophylactic treatment of seizures in a mammal, said composition comprising a pharmaceutically acceptable carrier; and, as active principle, the compound described above.
  • the pharmaceutical composition is in the form of a tablet, tablet, gel, oral liquid or syrup, capsule, suppository, injectable solution or inhalable or adhesive forms, and may optionally comprise other active principles.
  • Figure 1 shows the results of comparative stability tests of the compound of the invention vs Hp (PVNFKFLSH).
  • Statistical significance data are also shown, the asterisks indicating: ( * ) P ⁇ 0.05 vs Control ( *** ) P ⁇ 0.005 vs Control; ( **** ) P ⁇ 0.0001 vs Control.
  • Figure 2 shows the results of neuroprotection tests with the compound of the invention NFKF in the pilocarpine model, the survival / death profile of the animals being indicated by administration of the peptide of the invention.
  • A) the survival profile of the animals to which the control was administered (saline only) is shown;
  • B) the profile is shown survival rate of the animals administered cannabidiol 30mg / kg;
  • C) the survival profile of the animals to which the compound of the invention was administered NFKF 50C g / kg;
  • all profiles are shown in a single graph. It is interesting to note that in the group treated with the neuromodulator of the invention NFKF 500 ⁇ g / kg only two animals died.
  • Figure 3 shows the test results of the compound of the invention NFKF in the pilocarpine model, indicating the time for the first salivation to occur with the administration of cannabidiol (30mg / kg), or the compound of the invention NFKF (500 ⁇ g / kg).
  • cannabidiol 30mg / kg
  • compound of the invention NFKF 500 ⁇ g / kg
  • Figure 4 shows the test results of the compound of the invention NFKF as an anticonvulsant in the pilocarpine model, indicating the time for the first seizure to occur with the administration of cannabidiol (30mg / kg) or the peptide of the invention NFKF ( 500 ⁇ g / kg).
  • the asterisks indicate the statistical significance: ( ** ) P ⁇ 0.02 vs Control; ( *** ) P ⁇ 0.002 vs Control.
  • Figure 5 shows the test results of the compound of the invention NFKF compared to the results of hemopressin tests, both in the pilocarpine model.
  • the times for the first salivation occur with administration of the following treatment doses: control (saline); hemopressin (Hp or PVNFKFLSH, 0.551334 ⁇ / kg); hemopressin (0.91889 ⁇ / kg); the compound of the invention NFKF (0.540882 ⁇ / kg); NFKF (0.901469 ⁇ / kg); the compound PEP-19 (DIIADDEPLT, 0.9081 17 ⁇ l / kg).
  • the asterisks indicate the statistical significance: ( * ) P ⁇ 0.05 vs Control; ( ** ) P ⁇ 0.01 vs Control; the + sign indicates P ⁇ 0.05 vs Hp 0.91889 ⁇ / kg.
  • Figure 6 shows the test results of the compound of the invention NFKF as an anticonvulsant compared to the results of tests of hemopressin as an anticonvulsant, both in the pilocarpine model.
  • control saline
  • hemopressin Hp or PVNFKFLSH, 0.551334 ⁇ / kg
  • hemopressin 0.0.91889 ⁇ / kg
  • the compound of the invention NFKF 0.540882 ⁇ l-iol / kg
  • NFKF (0.901469 ⁇ - ⁇ / kg)
  • the compound PEP-19 DIIADDEPLT, 0.9081 17 ⁇ l / kg.
  • the asterisks indicate the statistical significance: ( * ) P ⁇ 0.05 vs Control; ( ** ) P ⁇ 0.01 vs Control; the + sign indicates P ⁇ 0.05 vs Hp 0.91889 ⁇ - ⁇ / kg.
  • Figure 7 shows an overview of the three-dimensional structure of a GPCR, in this case, the cannabinoid receptor of subtype 1.
  • Figure 8 shows the overlap of the AM6538 structure of the crystallographic structure (PDB 5TGZ), and the result obtained after validation by the Goldscore function (when the figure appears colored, the crystal structure is purple and the result of the Goldscore function in blue / cyan, although for the purposes of this application such colors are irrelevant).
  • Figure 9 shows the main interactions observed for AM6538 at the CB1 receptor binding site.
  • Figure 10 shows the major interactions observed for rimonabant at the CB1 receptor binding site.
  • Figure 11 shows the major interactions observed for cannabidiol at the CB1 receptor binding site.
  • Figure 12 shows the major interactions observed for the peptide of the invention NFKF at the binding site of the CB1 receptor.
  • Figure 13 shows the results of the process of obtaining CB2 receptor structure.
  • A) the three-dimensional structure of the obtained CB2 receptor is shown; in B) the Ramachandran Graph for the obtained human CB2 model is shown.
  • Figure 14 shows the major interactions between the CB2 receptor and the AM6538 linker.
  • Figure 15 shows the major interactions between the CB2 receptor and rimonabant.
  • Figure 16 shows the major interactions between the CB2 receptor and cannabidiol.
  • Figure 17 shows the major interactions between the CB2 receptor and the NFKF tetrapeptide.
  • the compound of the invention has demonstrated several surprising uses and results in in vitro and in vivo tests.
  • the compound of the invention is useful for the preparation of other compounds of pharmaceutical interest.
  • the compound of the invention is useful for the preparation of a pharmaceutical composition.
  • the pharmaceutical composition of the invention is cannabinoid and / or muscarinic receptor modulator, being particularly useful in modulating metabolic functions and / or neuromodulation of a mammalian animal.
  • AAi is an amino acid selected from the group consisting of F, W, L, I, V, P, G;
  • AA 2 is hydrogen or an amino acid selected from the group consisting of F, W, L, I, V, P, G;
  • R 1 is hydrogen, the amino acid V, or dipeptide PV
  • R 2 is absent when AA 2 is hydrogen or is hydrogen, the amino acid L, or the dipeptide LS when R 1 is hydrogen, and / or modified, cyclic forms thereof, amidated, methylated, PEGylated versions, salts thereof; and / or combinations thereof for the preparation of a composition of pharmaceutical interest.
  • compound of pharmaceutical interest means any molecular entity comprising the compound described as inventive concept common to the present application, including also molecular entities obtained by chemical derivatization thereof, with the inclusion of other functional groups, linear or branched side chains, alteration of hydrophilicity or hydrophobicity, among others, provided that they comprise as nucleus the entity R1-N-AA1-K-AA2-R2 as defined above, with the exception of entities natural and already known.
  • composition is to be understood as any and all compositions containing an active principle, for prophylactic, palliative and / or curative purposes, acting in a manner to maintain and / or restore the homeostasis, and may be administered orally, topically, parenterally, enterally and / or intrathecally.
  • a "pharmaceutically acceptable formulation” is meant a formulation containing pharmaceutically acceptable excipients and carriers well known to those skilled in the art, such as the development of convenient doses and treatments for use in particular compositions which can be described in a series of treatment regimens, including oral, parenteral, intravenous, intranasal, intravitreal and intramuscular, intracerebral, intracerebroventricular and intraocular and their administration and / or formulation.
  • modified peptide is to be understood as a non-naturally occurring, artificially modified or synthesized peptide, including cyclized, amidated, methylated, PEGylated, or salt forms thereof, as well as a peptide comprising one or more unnatural amino acid, such as d-amino acid forms.
  • the peptidic compound may be pegylated using techniques known to those skilled in the art, such as, for example, pegylation with reagents containing the succinimidyl group, which preferentially react with primary amines present in the N-terminal region of the peptide.
  • cyclic, cyclized or" circular peptide is to be understood as a peptide which has a covalent bond between the two ends of a linear peptide molecule by any method known in the art, particularly by the activity of enzymes.Cyclic peptide can be used instead of the linear peptide because it is more difficult to be degraded, since its ends or zones of attack by hydrolyzing enzymes are not as exposed as in a linear peptide.
  • agonist is to be understood as a drug, drug, hormone, neurotransmitter or other signaling molecule which forms a complex with a receptor site, thereby triggering an active response of a cell.
  • inverse agonist or antagonist as agent (s) (for example, drugs, drugs, hormones or enzymes) which binds to agonist receptors and produces pharmacological effects opposite to agonists, in such a way that the action of one partially or totally inhibits the effect of the other.
  • agent for example, drugs, drugs, hormones or enzymes
  • a compound is an inverse agonist when it acts in the presence of an agonist, but reducing its activity; an antagonist is a compound that will totally block the activity of the agonist.
  • the concept of "equivalent dose in humans” is the dose at which, in humans, the same magnitude of effects observed in animals at a given dose is expected, as advocated in Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers "published by the US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), July 2005 Pharmacology and Toxicology.
  • the conversion of the dose observed in animals (mg / kg) to Equivalent Dose in Humans (mg / kg) implies dividing the result obtained in rats by 6.2 and the result obtained in mice by 12.3. These values apply to a human with 60 kg of standard weight.
  • DEH Equivalent Human Dose
  • the compound of the invention is useful for modulating the cannabinoid system, either by modulating the CB1 receptor, the CB2 receptor, both concomitantly, by modulating the binding or action of other substances interacting in the cannabinoid system, by modulating proteases or peptidases which lead to the generation or degradation of active peptides in the cannabinoid system, or combinations thereof.
  • the term "modulating muscarinic receptor function" should be understood as an interaction leading to neuronal changes, including muscarinic acetylcholine receptor (mAChRs), which plays an important role in cognitive functions, such as such as learning and memory, control of dopamine release, modulation of locomotor activity, its modulation being also useful in the control of Alzheimer's disease and / or control of addiction or addiction to drugs of abuse. It is understood that the change is positive when an antagonist or inverse agonist effect occurs at muscarinic receptors and that the change is negative when an agonist effect occurs at muscarinic receptors.
  • the tests presented in the present patent application suggest that the compound of the invention interacts with and / or modulates muscarinic receptors.
  • this term is understood to include modulation of: energy and / or lipid metabolism; arterial hypertension, regulation of intestinal motility; Imune system; balance of the calcium cycle, conditions associated with the thyroid gland, peripheral organs and tissues, including reproductive organs, adipose tissue, liver, muscles and gastrointestinal tract, being useful in the treatment of obesity, diabetes, diseases or immune / inflammatory disorders, osteopenia, osteoporosis , cancer.
  • neuromodulator or “neuromodulator” is understood as the function of modulating the function neuronal / neurological, including modulation of brain activity, cortex, hippocampus, amygdala, pituitary, hypothalamus; adrenal gland.
  • Neuromodulation includes the beneficial modulation of neuroprotection against agents or conditions leading to pathophysiological processes. Neuroprotective agents or compounds are preferably used prior to (or during) the prodromal stage of disease, which often begins many years before the onset of symptoms.
  • a neuromodulator is potentially useful in the curative or prophylactic treatment of a variety of neurological conditions or diseases, including essential tremor, migraine, neuropathic pain, psychiatric disorders such as anxiety, schizophrenia or bipolar disorder, Alzheimer's, Parkinson's, autism, and is also potentially useful in modifying the pathophysiological processes involved in the occurrence of seizures and / or epilepsy, as well as in other clinical conditions related to disorders of neuronal excitability or neuronal lesions due to ischemia, hypoxia or other harmful conditions.
  • neurological conditions or diseases including essential tremor, migraine, neuropathic pain, psychiatric disorders such as anxiety, schizophrenia or bipolar disorder, Alzheimer's, Parkinson's, autism, and is also potentially useful in modifying the pathophysiological processes involved in the occurrence of seizures and / or epilepsy, as well as in other clinical conditions related to disorders of neuronal excitability or neuronal lesions due to ischemia, hypoxia or other harmful conditions.
  • the surprising pharmaceutical action of the invention may be linked to action on CB1 and / or CB2 and / or muscarinic or possibly linked to uptake modulation adenosine, GGPR55, PPAR ⁇ receptors, intracellular calcium level, or combinations thereof.
  • any therapeutic indication related to these targets may benefit from the present invention.
  • said peptide is selected from the group consisting of: NFK, NWK, NLK, NFKF, NWKF, NLKF, NFKW, NWKW, NLKW, NFKL, NWKL, NLKL, VNFK, VNWK, VNLK, NFKFL , NWKFL, NLKLL, NWKLL, NWKLL, NWKLL, NWKLL, NWKLL, NWKLL, NWKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL, NLKLL
  • a pharmaceutical composition modulating metabolic functions in a mammal comprising a pharmaceutically acceptable carrier; and, as active principle, the compound described above.
  • a curative or prophylactic pneumodulatory pharmaceutical composition in a mammal comprising a pharmaceutically acceptable carrier; and, as active principle, the compound described above.
  • a pharmaceutical composition for the curative or prophylactic treatment of seizures in a mammal comprising a pharmaceutically acceptable carrier; and, as active principle, the compound described above.
  • Neuromodulatory pharmaceutical composition comprising the NFK tripeptide, the NFKF tetrapeptide, the NFKL tetrapeptide, or combinations thereof.
  • a therapeutic modulator of metabolic functions of an animal comprising administering the peptide described above.
  • the peptide of the invention is preferably modified so that its molecular weight is greater, minimizing or preventing the passage thereof through the blood-brain barrier.
  • Therapeutic method for neuromodulation, neuroprotection and / or curative or prophylactic treatment of seizures comprising administering, to an animal, the compound described above.
  • the compound of the invention has been shown to be much more stable than hemopressin, which in addition causes the technical problems of fiber formation or fibrils, as it does with its known larger variants.
  • the neuromodulator / neuroprotective effect is evidenced by the absence of symptoms, brain damage, and deaths associated with the administration of substances known to be harmful, such as pilocarpine.
  • the invention provides the use of said compound for the preparation of a neuromodulatory, neuroprotective medicament and / or for the curative or prophylactic treatment of seizures in a mammal.
  • Administration, to an animal, of the compound of the invention provides neuromodulatory, neuroprotective and / or anticonvulsant activity; makes oral administration feasible; does not have or entails the drawbacks arising from the production, storage, transport and use of cannabinoid substances, in addition to providing additional advantages in the preparation of therapeutic products for mammals in their administration and / or effects.
  • administering the compound of the invention to an animal provides important and surprising technical advantages, including superior anticonvulsant activity with respect to hemopressin, the use of which as an anticonvulsant is the subject of the co-pending co-pending application of the same inventors.
  • the present invention describes the use of a compound for the preparation of pharmaceutical compositions useful for a varied set of medical conditions, including those related to the central nervous system.
  • the active compound of the invention is peptidic or predominantly peptidic, oral administration has provided brain effects in animals.
  • in vivo tests with the composition of the invention demonstrated surprising results regarding its neuroprotective activity.
  • the composition of the invention when administered previously to animals, provided surprising, potent and long protection against damage resulting from the subsequent administration of substances known to be harmful to neurons. Accordingly, the neuroprotection provided by the compound of the invention is particularly useful as a therapeutic alternative for various medical conditions, including those related to disorders of neuronal excitability, such as seizures.
  • in vivo tests with the compound of the invention demonstrated surprising results regarding its anticonvulsant activity.
  • the compound of the invention when used as an anticonvulsant, additionally provides the advantage of being a good candidate to substitute the cannabinoid compounds known for their acting as anticonvulsants, such as Canabidiol.
  • Cannabidiol despite its proven effects as an anticonvulsant, has been facing regulatory problems due to its origin, the Cannabis sativa plant.
  • the present invention provides an additional therapeutic approach for patients suffering from seizures and having difficulty in obtaining drugs, being based on a peptide, ie, does not use derivatives of Cannabis sativa.
  • the results showed that the compound of invention, when used as an anticonvulsant, provides other surprising technical advantages in use, including greater therapeutic effect, oral use, lower dosage, less occurrence of side effects such as prostration and nasal bleeding, among other technical advantages.
  • composition of the invention provides surprising technical advantages in use, including greater therapeutic effect, viability of oral use, lack of use of carrier oil (which in many cases causes side effects), lower dosage and lower occurrence of side effects such as prostration and nasal bleeding, among others.
  • the pharmaceutical composition of the invention is also useful for the treatment of diseases associated with modulation of the activity of the cannabinoid system, cannabinoid (CB) and / or muscarinic receptors - with various technical advantages and without known undesirable effects of the available congeners in the state of the art.
  • the compound as described above is useful for the preparation of a medicament modulator of metabolic functions.
  • the compound as described above is useful for the preparation of a neuromodulator, neuroprotective medicament and / or a medicament for the treatment of seizures.
  • the use of the compound of the invention in the preparation of a neuromodulatory, neuroprotective and / or anticonvulsant drug provides for the delivery of a medicament orally administrable to a mammal.
  • the results of the tests revealed significant brain action, suggesting that administration of the compound of the invention provides that the active element crosses the blood brain barrier.
  • the results show / support the use of the compound of the invention regardless of whether the compound of the invention is the active which acts directly on the target, ie, does not degrade during oral ingestion, or the compound is a precursor which, upon modification chemistry, acts on the target - in this case, being characterized as a pro-drug.
  • the present application discloses a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described above.
  • Said pharmaceutical composition also comprises a pharmaceutically acceptable carrier, optionally also comprising other pharmaceutically acceptable actives and / or salts thereof.
  • the compound of the invention is one or an active component of the pharmaceutical composition of the invention, which is administered in the form of a tablet, gel, capsule, oral liquid or syrup, a suppository, an injectable solution or other suitable forms of administration for pharmaceutical and medical purposes.
  • the neuromodulatory / neuroprotective / anticonvulsive effects of the composition of the invention have been evaluated in vivo by oral administration to animals.
  • the pharmaceutical composition of the invention was administered to mammals (Mus musculus or mouse) with an oral dose of treatment with different embodiments of the compound of the invention, as compared to other compounds or the saline control.
  • the test compounds were administered orally 10 minutes prior to (intraperitoneal) administration of pilocarpine.
  • Pilocarpine hydrochloride 320 mg / kg, Merck
  • dissolved in 0.9% sterile saline was administered intraperitoneally for induction of SE (status epileticus) (Turski et al., 1983).
  • SE status epileticus
  • the neurotoxic effects begin about 15-25 minutes after the injection of Pilo, with the occurrence of motor and limbic seizures, the animals evolving to a state of continuous (clonic) seizures that characterize SE Sanabria and Cavalheiro, 2000).
  • Example 1 Stability tests under extreme conditions
  • Hp hemopressin
  • PVNFKFLSH hemopressin
  • the compound R-N-AA -K-AA 2- F 2 is the NFKF tetrapeptide, which has been synthesized by chemical synthesis.
  • Said peptide was used in the preparation of a liquid pharmaceutical composition for oral use comprising between 2,7x10 "4 Molar said peptide and a pharmaceutically acceptable carrier.
  • said carrier solution is saline, the pharmaceutical composition being a solution for oral use.
  • Said composition was used for oral in vivo administration to mammals according to examples 3-6 below.
  • the pharmaceutical composition is in the form of a tablet, gel, oral liquid or syrup, capsule, suppository, injectable solution or inhalable or adhesive forms, optionally comprising other active principles.
  • Example 3 Neuromodulatory pharmaceutical composition comprising compound NFKF - in vivo test results
  • the neuromodulatory effect of the composition of the invention prepared according to example 2 was evaluated by prior administration of the inventive composition and subsequent administration of pilocarpine to animals.
  • Other test compounds were also evaluated as described below.
  • Administration of pilocarpine leads to severe brain injury, neurotoxicity and usually culminates in the death of the animals.
  • This substance was used in the experiments described below but its harmful neuronal / encephalic effects were inhibited by the prior administration of the composition of the present invention: the vast majority of the animals subjected to these experiments had no symptoms related to brain lesions and survived without apparent damage, in contrast to groups of animals treated with other known substances.
  • FIG. 2 shows the results of neuroprotection tests with the compound of the invention NFKF in the pilocarpine model, the survival / death profile of the animals being indicated by administration of the peptide of the invention.
  • A) the survival profile of the animals to which the control was administered (saline only) is shown;
  • B) the survival profile of the animals administered cannabidiol 30mg / kg is shown;
  • C) the survival profile of the animals to which the peptide of the invention is administered NFKF 500 ⁇ g / kg;
  • all profiles are shown in a single graph.
  • the anticonvulsive effect of the composition of the invention prepared according to example 2 was evaluated by prior administration of the inventive composition and subsequent administration of pilocarpine to animals.
  • Figure 3 presents the results of the pilocarpine model, indicating the time for the first salivation to occur with the administration of cannabidiol (30mg / kg) of the compound of the invention R-N-AA-K-AA 2 -F 2, in which embodiment it is the NFKF tetrapeptide (500 ⁇ g / kg).
  • the data between control and other test compounds do not present statistical significance among themselves under the conditions tested.
  • Figure 4 presents the results of tests with the pilocarpine model, indicating the time for the occurrence of the first convulsion with the administration of cannabidiol (30mg / kg) and the peptide of the invention NFKF (50C gg / kg).
  • the asterisks indicate: ( ** ) P ⁇ 0.02 vs Control; ( *** ) P ⁇ 0.002 vs Control.
  • Example 5 Comparative pharmaceutical composition comprising the compound NFKF with the pharmaceutical composition comprising Hp - in vivo test results
  • Figure 5 shows the test results of the compound of the invention NFKF as compared to the results of hemopressin tests, both in the pilocarpine model.
  • control saline
  • hemopressin Hp or PVNFKFLSH, 0.551334 ⁇ / kg
  • hemopressin 0.0.91889 ⁇ -iol / kg
  • the peptide of the invention NFKF 0.540882 ⁇ - ⁇ / kg
  • NFKF (0.901469 ⁇ / kg
  • PEP-19 DIIADDEPLT, 0.9081 17 ⁇ / kg.
  • the asterisks indicate the statistical significance: ( * ) P ⁇ 0.05 vs Control; ( ** ) P ⁇ 0.01 vs Control; the + sign indicates P ⁇ 0.05 vs Hp 0.91889 ⁇ / kg.
  • salivation induced by administration of pilocarpine is indicative of changes in muscarinic receptors. Consequently, the substantial change in the time profile for the occurrence of the first salivation observed with prior administration of the compound of the invention suggests modulation, either directly or indirectly, of muscarinic receptors.
  • Example 6 Comparative anticonvulsant pharmaceutical composition comprising the compound NFKF with the anticonvulsant pharmaceutical composition comprising Hp - in vivo test results
  • the anticonvulsive effects of the composition of the invention were compared to the pharmaceutical composition containing Hemopressin (Hp or PVNFKFLSH), the use of which as an anticonvulsant is co-pending co-pending application by the same inventors.
  • Hp or PVNFKFLSH Hemopressin
  • Figure 6 shows the test results of the compound of the invention NFKF as an anticonvulsant compared to the results of tests of hemopressin as an anticonvulsant, both in the pilocarpine model.
  • the percentages of time (relative to the control) for the first seizure occur with administration of the following treatment doses: hemopressin (Hp or PVNFKFLSH, 0.551334 ⁇ / kg); hemopressin (0.91889 ⁇ / kg); the peptide of the invention NFKF (0.540882 ⁇ / kg); NFKF (0.901469 ⁇ / kg); PEP-19 (DIIADDEPLT, 0.9081 17 ⁇ / kg) and control (saline).
  • the asterisks indicate: ( * ) P ⁇ 0.05 vs Control; ( ** ) P ⁇ 0.01 vs Control; the + sign indicates P ⁇ 0.05 vs Hp 0.91889 ⁇ / kg.
  • results of Figure 6 clearly show that oral administration of the compound of the present invention provides substantially higher seizure-modulating activity substantially greater than that observed with oral administration of Hp.
  • the same effect is observed with half the dose of the compound of the invention as compared to Hp.
  • the results of the tests performed in examples 3 to 6 above show significant and significant in vivo results, in dosage ranges of the order of 500 to 1000 ⁇ g of compound of the invention per kg of animal. Considering the tests in mice and the conversion to the Human Equivalent Dose mentioned above, effects of the same magnitude are expected in humans in the dosage range of 40 to 80 ⁇ g of compound of the invention per kg of human and, Safety ranges, concentrations between 4 to 800 ⁇ g / kg for administration to humans are considered in the present invention.
  • Example 7 In silico liqation tests / interaction of compound NFKF to CB1 receptor
  • the cannabinoid receptor 1 corresponds to GPCR (Expressed Receptors to Protein G) most expressed in the human brain and is found at high levels in the Central Nervous System in general ( Figure 7). It is activated by endocannabinoids and has been indicated as a promising therapeutic target for the treatment of various diseases such as pain and inflammation, multiple sclerosis and neurodegenerative diseases (agonist effect) and obesity, liver fibrosis and nicotine dependence (antagonistic effect) et al., 2016).
  • Figure 7 shows an overview of the three-dimensional structure of a GPCR, in this case, the cannabinoid receptor of subtype 1.
  • Table 1 RMSD values obtained from the validation of the scoring functions of the GOLD v. 5.5 for the redocking of AM6538 in the CB1 receptor.
  • Figure 8 shows visually the overlap between the crystallographic structure complex (PDB 5TGZ) and the resulting complex from the AM6538 redocking experiment using the validated methodology.
  • the resulting docking complex of the NFKF tetrapeptide in CB1 obtained a score of 100.66, substantially greater than the score achieved by the reference ligands. This fact can be explained by additional hydrogen bonds observed between the tetrapeptide and residues Ser-123, Thr-197, Ser-167 and Ser-383. In addition, the hydrophobic interactions observed for AM6538 are also present in the NFKF interaction mode ( Figure 12).
  • Example 8 In silico liqation tests / interaction of compound NFKF to CB2 receptor
  • the construction of the 3D model of CB2 was done from a search in the UniProt database of the amino acid sequence of this receptor.
  • the criterion used for sequence selection was the species (Homo sapiens).
  • the sequence selected for carrying out the molecular modeling studies was that of code P34972.
  • the Template Identification tool of the SwissModel server was used to identify and select the protein template.
  • the sequence identified by the server as having the highest structural identity to the human CB2 sequence was that of PDT 5TGZ code (HUA et al., 2016) belonging to the species Homo sapiens, corresponding to the CB1 receptor.
  • the target and template sequences were then aligned using ClustalW2 software linked to the UniProt database to compare the sequences to establish the percentage of identity between them.
  • the 3D homology model of human CB2 was constructed using the Automated Mode tool available on the Swiss-model server page and, for the validation of the generated model, were analyzed the overall structural quality and the stereochemical quality of the model through the value presented for the GMQE parameter and the analysis of the Ramachandran graph.
  • the stereochemical quality of the model was analyzed using the Ramachandran graph (Figure 13B).
  • the Ramachandran graph corresponds to a mathematical model, which relates the dihedral angles ⁇ (angle C-N-Ca-C) on the x-axis and ⁇ (angle N-Ca-C-N) on the y-axis.
  • This graph is divided into regions capable of representing the probability of a combination between the angles ⁇ and ⁇ (RAMACHANDRAN; RAMAKRISHNAN; SASISEKHARAN, 1963). These regions are classified as: favorable, permitted, generously permitted and prohibited.
  • the Ramachandran graph constructed for the human CB2 model showed the presence of approximately 96% of the amino acid residues in the most favorable regions and more than 4% of the residues in acceptable regions. No amino acid residue was found in forbidden regions, indicating the stereochemical validation of the model created.
  • the docking studies on CB2 of the NFKF tetrapeptide, AM6538 antagonist, the cannabidiol endogenous ligand and the rimonabant antagonist were performed.
  • Table 2 summarizes the comparison between the scores obtained by the docking studies on both receptors (CB1 and CB2) in examples 7 and 8 above:
  • Table 2 Comparison between the scores obtained in the docking studies for CB1 and CB2 receptors.
  • the results of the in silico experiments of examples 7 and 8 indicate that the NFKF tetrapeptide is a CB1 receptor linker.
  • CB2 receptors less favorable interactions of this compound were evidenced in CB2 receptors, indicating a possible selectivity profile.
  • the results of the experiments of examples 7 and 8, especially those shown in Figures 12 and 17, show that NFK amino acids participate much more strongly in the binding of CB1 and CB2 than the amino acid F in the C-terminal position, indicating that this tripeptide is a potential candidate for ligand / modulator of such receptors.
  • binding techniques were used to measure the affinity of the NFKF tetrapeptide (powder in 100% purity and prepared as stock solution 10mM in DMSO) by the cannabinoid receptor CB1 at the concentrations of 1 and 10 ⁇ .
  • Results are expressed as the percentage of specific control binding according to the formula:
  • IC50 values concentration that causes half of maximum inhibition of specific control binding
  • Hill (nH) coefficients were determined by nonlinear regression of the competition curves generated with the mean values of the replicates using the Hill equation .
  • results showing inhibition or stimulation greater than 50% are considered to represent significant effect of the test compound. Results showing inhibition or stimulation between 25% and 50% are indicative of low to moderate effect of the test compound. Results showing inhibition or stimulation of less than 25% can be considered as minor. Results showing inhibition greater than or equal to 50% are indicative non-specific or allosteric effects of the test compound.
  • Example 10 In vitro in vitro binding of the compound NFKF to the CB2 receptor
  • the in vitro affinity profile of the compound of the invention R-N-AA-K-AA 2 -R 2 , in which is the NFKF tetrapeptide, is evaluated with the cannabinoid receptor CB2.
  • binding techniques were used to measure the affinity of the NFKF tetrapeptide (powder in 100% purity and prepared as stock solution 10mM in DMSO) by the cannabinoid receptor CB2 at concentrations of 1 and 10 ⁇ .
  • in vitro test results demonstrate that the compound of the invention can be used as a binder of diagnostic interest, for example radioactive labeling or with chromophores for subsequent identification of the sites of binding in cells and / or tissues.
  • the inventive concept herein disclosed and exemplified in one or more ways was treated as an industrial secret and was not previously disclosed until the filing of this patent application.
  • This industrial secret is immaterial asset of the depositor.
  • the possible future publication of the patent application does not in itself constitute authorization for use by third parties, serving only as: (i) scientific knowledge to third parties of the existence of said industrial secret at the time of filing; (ii) unequivocal indication of its holder; and (iii) stimulating the development of new improvements based on the concept to avoid reinvestment in the development of the same asset already held by the depositor.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Biomedical Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pain & Pain Management (AREA)
  • Child & Adolescent Psychology (AREA)
  • Emergency Medicine (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention trouve une application dans les domaines de la chimie, de la pharmacie, de la biotechnologie et de la médecine. Plus particulièrement, la présente invention concerne un composé, son utilisation, un produit intermédiaire de synthèse pour la préparation de composés d'intérêt pharmaceutique, l'utilisation de ce composé pour préparer un ligand d'intérêt diagnostic et/ou thérapeutique, son utilisation pour préparer des médicaments de modulation du métabolisme ou un médicament neuromodulateur, une composition pharmaceutique contenant ledit composé peptidique et une méthode thérapeutique. Le composé de l'invention se lie et/ou module l'activité de récepteurs cannabinoïdes (CB), notamment CB1 et/ou CB2, et/ou des récepteurs muscariniques, et s'est révélé étonnamment utile pour la modulation des systèmes respectifs. La composition de l'invention est utile pour la modulation de la fonction métabolique et/ou pour la neuromodulation. Dans un mode de réalisation, l'administration orale du composé de l'invention à un mammifère permet d'obtenir un excellent résultat neuroprotecteur et anticonvulsivant. Entre autres avantages et effets techniques, l'invention permet de supprimer les inconvénients découlant de l'utilisation de substances cannabinoïdes, telles que le cannabidiol, et produit un effet thérapeutique plus important avec un dosage réduit et moins d'effets secondaires.
PCT/BR2017/050314 2016-10-13 2017-10-11 Utilisation d'un composé, produit intermédiaire de synthèse, composition pharmaceutique et méthode thérapeutique de neuromodulation WO2018068120A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
IL273868A IL273868B1 (en) 2016-10-13 2017-10-11 Use of a compound, a synthetic intermediate, a pharmaceutical preparation and a therapeutic method of neuromodulation
PCT/BR2018/050156 WO2018209415A1 (fr) 2017-05-15 2018-05-14 Composé, produit intermédiaire de synthèse, utilisation, composition pharmaceutique et méthode thérapeutique de neuromodulation
BR112019002655A BR112019002655A2 (pt) 2017-05-15 2018-05-14 composto, intermediário de síntese, uso e composição farmacêutica neuromoduladora
JP2019564034A JP7241032B2 (ja) 2017-05-15 2018-05-14 化合物、合成中間体、使用、医薬組成物及び神経調節治療方法
EP18802073.9A EP3626727A4 (fr) 2017-05-15 2018-05-14 Composé, produit intermédiaire de synthèse, utilisation, composition pharmaceutique et méthode thérapeutique de neuromodulation
CN201880047283.1A CN110891963B (zh) 2017-05-15 2018-05-14 化合物、合成中间体、用途、药物组合物以及神经调节治疗方法
US16/612,220 US20220098237A1 (en) 2017-05-15 2018-05-14 Compound, synthesis intermediate, use, pharmaceutical composition and neuromodulatory therapeutic method

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
BR102016023848-0A BR102016023848A2 (pt) 2016-10-13 2016-10-13 Anticonvulsivante, uso e composição farmacêutica contendo o mesmo
BRBR102016023848-0 2016-10-13
BR102017010169-0A BR102017010169A2 (pt) 2017-05-15 2017-05-15 composto, intermediário de síntese, uso na preparação de anticonvulsivante, composição farmacêutica anticonvulsivante
BRBR102017010169-0 2017-05-15

Publications (1)

Publication Number Publication Date
WO2018068120A1 true WO2018068120A1 (fr) 2018-04-19

Family

ID=61905035

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/BR2017/050314 WO2018068120A1 (fr) 2016-10-13 2017-10-11 Utilisation d'un composé, produit intermédiaire de synthèse, composition pharmaceutique et méthode thérapeutique de neuromodulation

Country Status (2)

Country Link
IL (1) IL273868B1 (fr)
WO (1) WO2018068120A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018209415A1 (fr) * 2017-05-15 2018-11-22 Remer Consultores Assessoria Empresarial Ltda. Composé, produit intermédiaire de synthèse, utilisation, composition pharmaceutique et méthode thérapeutique de neuromodulation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070213302A1 (en) * 2006-03-10 2007-09-13 Jenrin Discovery Cannabinoid receptor antagonists/inverse agonists useful for treating obesity
WO2011011847A2 (fr) * 2009-07-31 2011-02-03 Sociedade Beneficiente De Senhoras Hospital Sirio Libanes Composition pharmaceutique de traitement d’états pathologiques et procédé de traitement de troubles alimentaires et de maladies associées
WO2013021196A2 (fr) * 2011-08-08 2013-02-14 University Of Coimbra Différenciation d'oligodendrocytes
WO2014008567A1 (fr) * 2012-07-13 2014-01-16 Proteimax Biotecnologia Ltda Peptide modifié, ligand de récepeurs cb, trousse, procédé in vitro pour l'évaluation de la liaison aux récepteurs cb, utilisations et composition pharmaceutique pour moduler l'activité de récepteurs cb

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070213302A1 (en) * 2006-03-10 2007-09-13 Jenrin Discovery Cannabinoid receptor antagonists/inverse agonists useful for treating obesity
WO2011011847A2 (fr) * 2009-07-31 2011-02-03 Sociedade Beneficiente De Senhoras Hospital Sirio Libanes Composition pharmaceutique de traitement d’états pathologiques et procédé de traitement de troubles alimentaires et de maladies associées
US20150297669A1 (en) * 2009-07-31 2015-10-22 Sociedade Beneficente De Senhoras Hospital Sirio Libanes Pharmaceutical composition for treating medical conditions and a method for treating alimentary disorders and related diseases
WO2013021196A2 (fr) * 2011-08-08 2013-02-14 University Of Coimbra Différenciation d'oligodendrocytes
WO2014008567A1 (fr) * 2012-07-13 2014-01-16 Proteimax Biotecnologia Ltda Peptide modifié, ligand de récepeurs cb, trousse, procédé in vitro pour l'évaluation de la liaison aux récepteurs cb, utilisations et composition pharmaceutique pour moduler l'activité de récepteurs cb

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
GOMES I ET AL.: "Novel endogenous peptide agonists of cannabinoid receptors", FASEB J., vol. 23, no. 9, 2009, pages 3020 - 3029, XP055186735 *
IVONE GOMES ET AL.: "Hemoglobin-derived Peptides as Novel Type of Bioactive Signaling Molecules", AAPS J., vol. 12, no. 4, 2010, pages 658 - 669, XP035719135 *
MELISA J WALLACE ET AL.: "Assessment of the role of CB1 receptors in cannabinoid anticonvulsant effects", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 428, no. 1, 2001, pages 51 - 57, XP055475315 *
MELISA J. WALLACE ET AL.: "The Endogenous Cannabinoid System Regulates Seizure Frequency and Duration in a Model of Temporal Lobe Epilepsy", JOURNAL . OF PHARMACOLOGY AND EXPERIMENTAL . THERAPEUTIC., vol. 307, no. 1, 2003, pages 129 - 137, XP055360835 *
RIOLI ET AL.: "Novel natural peptide substrates for endopeptidase 24.15, neurolysin, and angiotensin-converting enzyme", J BIOL CHEM., vol. 278, no. i 0, 2003, pages 8547 - 8555, XP002353088 *
SZLAVICZ ET AL.: "Further Characterization of Hemopressin Peptide Fragments in the Opioid and Cannabinoid Systems", ANESTH ANALG., vol. 121, no. 6, 2015, pages 1488 - 1494, XP055476031 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018209415A1 (fr) * 2017-05-15 2018-11-22 Remer Consultores Assessoria Empresarial Ltda. Composé, produit intermédiaire de synthèse, utilisation, composition pharmaceutique et méthode thérapeutique de neuromodulation
CN110891963A (zh) * 2017-05-15 2020-03-17 雷默咨询顾问有限公司 化合物、合成中间体、用途、药物组合物以及神经调节治疗方法
CN110891963B (zh) * 2017-05-15 2024-02-20 雷默咨询顾问有限公司 化合物、合成中间体、用途、药物组合物以及神经调节治疗方法

Also Published As

Publication number Publication date
IL273868B1 (en) 2024-03-01
IL273868A (en) 2020-05-31

Similar Documents

Publication Publication Date Title
US20220233475A1 (en) Novel d3 dopamine receptor agonists to treat dyskinesia in parkinson's disease
Goebel-Goody et al. Therapeutic implications for striatal-enriched protein tyrosine phosphatase (STEP) in neuropsychiatric disorders
Winkler et al. The diverse biological properties of the chemically inert noble gases
Stornaiuolo et al. Endogenous vs exogenous allosteric modulators in GPCRs: a dispute for shuttling CB1 among different membrane microenvironments
Seebohm et al. Beyond hot and spicy: TRPV channels and their pharmacological modulation
JP6619097B2 (ja) スペキシン基盤のガラニン２型受容体のアゴニスト及びその用途
WO2018209415A1 (fr) Composé, produit intermédiaire de synthèse, utilisation, composition pharmaceutique et méthode thérapeutique de neuromodulation
Abad-García et al. Interactions of a boron-containing levodopa derivative on D 2 dopamine receptor and its effects in a Parkinson disease model
Gibbs et al. Structure, function and physiology of 5-hydroxytryptamine receptors subtype 3
Zhang et al. Stereochemistry and innate immune recognition:(+)-norbinaltorphimine targets myeloid differentiation protein 2 and inhibits toll-like receptor 4 signaling
Xu et al. Structure and activity studies of disulfide-deficient analogues of αO-conotoxin GeXIVA
Levy et al. The minimal amyloid‐forming fragment of the islet amyloid polypeptide is a glycolipid‐binding domain
WO2018068120A1 (fr) Utilisation d'un composé, produit intermédiaire de synthèse, composition pharmaceutique et méthode thérapeutique de neuromodulation
Boopathi et al. Calcium inhibits penetration of Alzheimer's Aβ1–42 monomers into the membrane
EP3527217B1 (fr) Compositions pharmaceutiques comprenant des peptides pvnfkflsh ou pvnfkllsh pour leur utilisation dans la prevention et le traitement des convulsions
ZA200407103B (en) Anti-infarction molecules
Chi et al. Unveiling the G4-PAMAM capacity to bind and protect Ang-(1-7) bioactive peptide by molecular dynamics simulations
Padilla-Morales et al. Effects of lipid-analog detergent solubilization on the functionality and lipidic cubic phase mobility of the Torpedo californica nicotinic acetylcholine receptor
BR102012017421A2 (pt) Peptídeo, composicão farmacêutica, ligante de receptor cb, metodo para modular a funcao de receptor cb, uso, método para o tratamento de obesidade, e, método para promover a redução de peso estetica em um indivíduo
Huang et al. Targeting TRP Channels: Recent Advances in Structure, Ligand Binding and Molecular Mechanisms
Hok et al. Selective deuteration improves the affinity of adenosine A2A receptor ligands: A computational case study with istradefylline and caffeine
BR102020015866A2 (pt) Peptídeos com atuação sobre o receptor hipotalâmico y5 com atividade supressora do apetite
Murray et al. Exploring the binding interactions of NOP receptor with designed natural phytochemical-neuropeptide conjugates: an in silico and SPR study
JP2022535086A (ja) 修飾ペプチドおよび関連する使用方法
Marcelli A novel selective cell-permeable peptide disrupts presynaptic JNK2-STX1a interaction, providing neuroprotection and preventing glutamate-mediated excitotoxicity

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17860070

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17860070

Country of ref document: EP

Kind code of ref document: A1