WO2023144166A1 - Utilisation d'agonistes du récepteur de la sérotonine 5-ht1a pour traiter des maladies associées à la mort subite inattendue en épilepsie - Google Patents

Utilisation d'agonistes du récepteur de la sérotonine 5-ht1a pour traiter des maladies associées à la mort subite inattendue en épilepsie Download PDF

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WO2023144166A1
WO2023144166A1 PCT/EP2023/051732 EP2023051732W WO2023144166A1 WO 2023144166 A1 WO2023144166 A1 WO 2023144166A1 EP 2023051732 W EP2023051732 W EP 2023051732W WO 2023144166 A1 WO2023144166 A1 WO 2023144166A1
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syndrome
receptor agonist
formula
epilepsy
chosen
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PCT/EP2023/051732
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English (en)
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Adrian Newman-Tancredi
Mark A. Varney
Khaleelurrahman Abdulrazak
Xin Tao
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Neurolixis
The Regents Of The University Of California
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Priority claimed from US17/586,477 external-priority patent/US11974992B2/en
Application filed by Neurolixis, The Regents Of The University Of California filed Critical Neurolixis
Publication of WO2023144166A1 publication Critical patent/WO2023144166A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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

Definitions

  • the present invention concerns the field of therapeutic treatment of diseases associated with Sudden Unexpected Death in Epilepsy (SUDEP), such as Fragile X Syndrome (FXS).
  • SUVEP Sudden Unexpected Death in Epilepsy
  • FXS Fragile X Syndrome
  • Seizure or epileptic seizure is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Fatal complications of epilepsy may lead to SUDEP, which is defined as the sudden and unexpected, non-traumatic and non-drowning death of a person with epilepsy, without a toxicological or anatomical cause of death. Not all seizures lead to SUDEP. It has been hypothesized that certain seizure types or seizures occurring in certain patients may be associated with an increased risk of SUDEP.
  • Seizures associated with SUDEP typically occur in certain diseases.
  • FXS Fragile X syndrome
  • Subjects with FXS suffer from a range of symptoms, including sensory hypersensitivity and a propensity to epileptic seizures.
  • Transgenic mice lacking FMRP function are an animal model of FXS and are prone to audiogenic seizures (i.e., seizures induced by loud noise) which, if prolonged, result in death.
  • SCN1A SCN1 B, SCN8A, SCN2A, GNB5, KCNA1 , CDKL5 and DEPDC5 genes which can lead to SUDEP.
  • Dravet syndrome Guillain-Barre syndrome, Ohtahara syndrome, Angelman syndrome, myoclonic astatic epilepsy (MAE), and Lennox-Gastaut syndrome.
  • 5-HT 5- hydroxytryptamine
  • vilazodone which acts as a 5-HTIA receptor agonist, induces seizures in humans (McKean et al. Pharmacotherapy. 2015 Mar;35(3):e6- 8. doi: 10.1002/phar.1549. PMID: 25809181 ).
  • WO2016/138138 also discloses the treatment of epilepsy with 5-HT receptor agonists, binding to 5-HT 2 A and 5-HT 2 B receptors but without significant binding to 5-HTIA receptors. In any case, there is no mention of selective 5-HTIA agonists in this patent.
  • NLX-101 also known as F-15599
  • NLX-101 has been disclosed in WO03/106449. It is a compound which highly selectively targets serotonin 5-HTIA receptors and has been tested in preclinical and clinical studies. It has a distinctive property, known as ‘biased agonism’, whereby it directs 5-HTIA receptors to preferentially activate specific intracellular signaling
  • SUBSTITUTE SHEET (RULE 26) pathways, notably ERK1/2 phosphorylation, as opposed to other signaling pathways.
  • the biased agonist properties of NLX-101 are associated with activation of specific brain regions (Llado-Pelfort et al J Pharmacol. 2010 Aug; 160(8):1929-40. doi: 10.1 11 1/j.1476- 5381 .2010.00738.X.PMID: 20649591 ).
  • NLX-101 unexpectedly reduces audiogenic seizures in FMR1 knock-out mice, and have established that selective 5-HTIA receptor agonists may therefore be useful for treating FXS and other diseases associated with SUDEP.
  • the present invention provides for a method of treatment or prevention of a disease associated with SUDEP chosen from the group consisting in seizures, Fragile X syndrome, Dravet syndrome, Guillain-Barre syndrome, Ohtahara syndrome, Angelman syndrome, myoclonic astatic epilepsy (MAE), Lennox-Gastaut syndrome and diseases associated with the FMR1 , SCN1A, SCN1 B, SCN8A, SCN2A, GNB5, KCNA1 , CDKL5 or DEPDC5 gene dysfunction, comprising administering a therapeutically effective amount of a selective 5-HTIA receptor agonist in a patient suffering from such a disease.
  • a disease associated with SUDEP chosen from the group consisting in seizures, Fragile X syndrome, Dravet syndrome, Guillain-Barre syndrome, Ohtahara syndrome, Angelman syndrome, myoclonic astatic epilepsy (MAE), Lennox-Gastaut syndrome and diseases associated with the FMR1 , SCN
  • the present invention also provides for a method of treatment or prevention of seizures comprising administering a therapeutically effective amount of a selective 5-HTIA receptor agonist in a patient suffering from a disease where SUDEP occurs.
  • said disease where SUDEP occurs include Fragile X syndrome, Dravet syndrome, Guillain-Barre syndrome, Ohtahara syndrome, Angelman syndrome, Rett syndrome, myoclonic astatic epilepsy (MAE), Lennox-Gastaut syndrome and diseases associated with the FMR1 , SCN1 A, SCN1 B, SCN8A, SCN2A, GNB5, KCNA1 , CDKL5 or DEPDC5 gene dysfunction
  • said diseases are chosen from Fragile X syndrome, Dravet syndrome, Guillain-Barre syndrome and Ohtahara syndrome.
  • NLX-101 did not exhibit any anti-seizure activity in wild-type (i.e., non-transgenic) mice, using two widely used models of epileptic seizures induced by corneal electrical stimulation.
  • wild-type mice i.e., non-transgenic mice
  • NLX-101 potently and efficaciously reduced seizures and protected over 75 percent of the mice from death.
  • NLX-101 corneal electrically induced seizures in wildtype mice suggests a general lack of anti-seizure activity for the compound. Consequently, the anti-seizure activity of NLX-101 on audiogenic seizures in transgenic FMR1 mice was unexpected and suggests an activity of selective 5-HTIA receptor agonists on certain seizure types, particularly those associated with SUDEP.
  • NLX-101 The capacity of NLX-101 to reduce seizures and death in FMR1 knock-out mice may arise from the very selective agonist properties of NLX-101 at 5-HTIA receptors. Moreover, its biased agonist activity for activation of ERK1/2 phosphorylation may contribute to its antiseizure and anti-SUDEP properties.
  • associated with SUDEP refers to a disease that may lead to an increased risk of SUDEP when compared with the general patient population, typically at least 10% more preferably at least 20%, more preferably at least 30% more SUDEP than in the general patient population. Such increased risk may correspond to certain seizure types and/or they may occur in certain patient populations.
  • diseases refers to health disorders, and encompasses both the established medical conditions having defined reasons, as well as syndromes (ie) a collection of symptoms which may not necessarily have an identifiable cause.
  • the treatment of such diseases includes the removal of the causes and/or the attenuation of the symptoms.
  • the 5-HTIA receptor agonist is a selective biased 5-HTIA receptor agonist.
  • the selective 5-HTIA receptor agonist is selected from the group consisting in compounds of formula (I) :
  • X represents a halogen atom
  • Z represents a -(CH 2 -Y)n-Ar group where: n is 0 or 1 ;
  • Y is chosen from -CH 2 -, -NH-, -S- or -O-;
  • Ar represents a 5 to 10 membered aryl or heteroaryl ring optionally substituted by one or more C1 -C6 alkyl groups;
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 6 carbon atoms in the chain, optionally substituted with one or more substituents which may be the same or different, and include halo, hydroxy, cyano, amino, alkoxy.
  • substituents which may be the same or different, and include halo, hydroxy, cyano, amino, alkoxy.
  • alkyl groups include methyl, ethyl, n-propyl, /-propyl.
  • Aryl means an aromatic monocyclic or bicyclic ring system of 5 to about 10 carbon atoms, preferably of about 6 to about 10 carbon atoms.
  • exemplary aryl groups include phenyl or naphthyl.
  • Heteroaryl means an aromatic monocyclic or bicyclic ring system of about 5 to about 10 atoms, preferably about 5 to about 10 carbon atoms, in which at one or more of the atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred ring sizes of rings of the ring system include about 5 to about 6 ring atoms.
  • the designation of the aza, oxa or thia as a prefix before heteroaryl defines that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom.
  • a nitrogen atom of an heteroaryl may be a basic nitrogen atom and may also be optionally oxidized to the corresponding N-oxide.
  • heteroaryl groups include pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyl, furazanyl, pyrrolyl, 1 ,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1 ,2-a]pyridine, imidazo[2,1 -b]thiazolyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl,
  • SUBSTITUTE SHEET (RULE 26) imidazopyridyl, benzoazaindole, 1 ,2,4-triazinyl, benzthiazolyl, furanyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1 ,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl.
  • Preferred heteroaryl groups include pyrazinyl, pyridyl, pyrimidinyl.
  • the compound of formula (I) is chosen from compounds (IA) and (II) below which are closely related and which also exhibit similar biased agonist properties for activation of ERK1/2 phosphorylation :
  • X is chosen from F and Cl;
  • Y is chosen from -CH2-, -NH-, -S-, or -O-;
  • Ar is chosen from phenyl and N-containing 6-membered monocyclic heteroaryl groups, optionally substituted by one or more C1-C6 alkyl groups;
  • X is chosen from F and Cl;
  • Ar is chosen from the group consisting of:
  • compounds of formula (II) can be chosen from:
  • the compounds may be in the form of their free base, or alternatively, in the form of pharmaceutically acceptable salts such as hydrochloride, oxalate, dihydrochloride, fumarate, maleate, tosylate, salicylate, sulfonate or benzoate.
  • pharmaceutically acceptable salts such as hydrochloride, oxalate, dihydrochloride, fumarate, maleate, tosylate, salicylate, sulfonate or benzoate.
  • patients suffering from a disease associated with SUDEP may exhibit a FRM1 gene dysfunction.
  • Actual dosage levels of the compounds may be varied so as to obtain an amount of the active ingredient that is effective to obtain a desired therapeutic response for a particular composition and method of administration.
  • the selected dosage level therefore depends upon the desired therapeutic effect, on the route of administration, on the desired duration of treatment and other factors, e.g., the condition of the patient.
  • a therapeutically effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances.
  • determining the therapeutically effective amount a number of factors are considered by the attending diagnostician, including, but not limited to: the species of subject; its size, age, and general health; the specific disease involved; the degree of involvement or the severity of the disease; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristic of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • SUBSTITUTE SHEET (RULE 26)
  • the amount of the compounds which is required to achieve the desired biological effect will vary depending upon a number of factors, including the type of formulation of the drug to be administered, the type of disease, the disease state of the patient and the route of administration.
  • the preferred dosage of a drug to be administered is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, and formulation of the compound excipient, and its route of administration.
  • the daily dose of the selective 5-HTIA receptor agonist may generally be comprised between 0.1 mg/day and 10 mg/day in a human patient, more particularly between 0.5 and 3 mg/day.
  • the method of the invention also comprises the administration of one or more further active ingredient, typically administered in the treatment or prevention of seizures.
  • the selective 5-HTIA receptor agonist can be formulated into a pharmaceutical composition by admixture with one or more pharmaceutically acceptable excipients.
  • compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington: The Science and Practice of Pharmacy, 20 th ed.; Gennaro, A. R., Ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2000.
  • the selective 5-HTIA receptor agonist may be administered by various administration routes such as oral; parenteral including sub-cutaneous, intramuscular, intra-venous; sublingual, topical; local; intratracheal; intranasal; transdermal or rectal, the active ingredients being combined with a pharmaceutically acceptable excipient or vehicle in one or two pharmaceutical compositions.
  • the formulations suitable for parenteral administration are sterile and include emulsions, suspensions, aqueous and non-aqueous injection solutions, which may contain suspending agents and thickening agents and anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic, and have a suitably adjusted pH, with the blood of the intended recipient.
  • the compositions of the invention may be used as creams, gels, ointments or lotions.
  • SUBSTITUTE SHEET include discrete units such as capsules, such as soft or hard gelatine, tablets, each containing a predetermined amount of selective 5-HTIA receptor agonist. They also include powder; granules; solutions or suspensions in an aqueous liquid or a non-aqueous liquid, or oil-in-water liquid emulsion or water-in-oil liquid emulsion. Gastrointestinal resistant formulations are also contemplated for oral formulations, in particular for duloxetine.
  • “Pharmaceutically” or “pharmaceutically acceptable” refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate.
  • pharmaceutically acceptable excipient includes in particular diluents, adjuvants, carriers, or vehicles.
  • diluents include in particular diluents, adjuvants, carriers, or vehicles.
  • the use of such ingredients for pharmaceutical active substances is well known in the art.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • prevention refers to the prophylaxis of a condition and in particular aims at decreasing the risk that said condition occurs or at decreasing the extent to which the condition will occur.
  • “Therapeutically effective amount” means an amount of a compound/pharmaceutical composition according to the present invention effective in producing the desired therapeutic effect.
  • the term “patient”, or “patient in need thereof” is intended for a human or non-human mammal affected or likely to be affected with the above disorders.
  • the patient is a human.
  • the compounds may be administered in unit dosage forms, wherein the term “unit dose” means a single dose which is capable of being administered to a patient, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising either the active compound itself, or as one or two pharmaceutically acceptable compositions.
  • the appropriate unitary dosage forms comprise the oral forms; the sublingual, buccal, intratracheal, intraocular, intranasal forms, by inhalation, the topical, transdermal, sub-cutaneous, intramuscular or intra-venous, and the rectal forms and the implants.
  • Figure 1 illustrates the lack of anti-seizure activity of NLX-101 in two models of seizures in wild-type mice.
  • Figure 2 illustrates the dose-dependent reduction by NLX-101 of tonic-clonic seizures (TCS) and death rate in FRM1 transgenic mice (ns: not significant; *** p ⁇ 0.001 , **** p ⁇ 0.0001 , Log-rank (Mantel-Cox) test).
  • CES Corneal Electrical Stimulation
  • NINDS National Institute of Neurological Disorders and Stroke
  • the CES test was carried out using wild-type male CF-1 mice. Seizures were induced by a low frequency (6 Hz, 0.2 msec rectangular pulse), long-duration (3 sec), 44 mA current (double the current producing seizures in 97% of animals) delivered through corneal electrodes (Barton ME, Klein BD, Wolf HH, White HS.
  • SUBSTITUTE SHEET (RULE 26) initial momentary stun followed immediately by jaw clonus, forelimb clonus, twitching of the vibrissae, and “Straub tail”. Animals not displaying this behavior within the one-minute observation period are considered “protected” from seizures.
  • NLX-101 0.02, 0.06, 0.5, 1 and 2 mg/kg i.p.
  • timepoints 30 and 120 min after drug administration
  • MES Neurological Disorders and Stroke
  • Seizures were induced by a high frequency (60 Hz) of alternating current at 50 mA over a short duration (0.2 sec) delivered through corneal electrodes. Prior to stimulation, corneas were irrigated with 0.5% tetracaine hydrochloride for local anesthesia and 0.9% saline to improve electrical conductivity. Seizures induced by MES are characterized by tonic extension of forelimbs and hindlimbs that is followed by brief episodes of clonic activity of the forelimbs and hindlimbs. An animal is considered “protected” from MES-induced seizures upon abolition of the hindlimb tonic extensor component of the seizure.
  • FMR1 knock-out mice were bred and weaned at postnatal day 21 (P21 ), and all mice were tested between P21 to P23.
  • NLX-101 was administered at doses of 0.6, 1.2, 1.8 and 2.4 mg/kg i.p.
  • Control FMR1 KO mice received saline.
  • NLX-101 or saline was injected 10 min before subjecting the mice to the auditory stimulus.
  • mice were color coded prior to drug or saline administration. Mice (up to 4 /cage) were then put in a cage with a lid; after 10 min, a speaker was placed on top of the lid, and the cage placed in a sound attenuation
  • SUBSTITUTE SHEET (RULE 26) booth (Gretch-Ken Inc., OR); the auditory stimulus was a continuously alternating up and down frequency modulated sweep with frequencies between 2-8 kHz, presented at an intensity between 105-110 dB for 15 min. The procedure lasted a total of 20 min starting with 5 min of habituation (without a sound stimulus). The full 20-min procedure was video recorded for off-line analysis.
  • the typical behavior of FMR1 knock-out mice subjected to loud audio stimulus includes tonic-clonic seizures (TCS: the mouse lays on the cage bottom with hindlimb extension), and death by respiratory arrest (manifested by a deep respiratory gasp and relaxation of pinna).
  • the latency time (from the stimulus onset) to the occurrence of TCS and death were recorded with a stopwatch (precision: 1 sec). Survival analysis was used to analyze the probability of TCS or death by log-rank test.
  • NLX-101 In wild-type mice, NLX-101 , over a wide range of doses (0.02 to 2 mg/kg i.p.) and at 30- and 120-min post-injection, did not affect the occurrence of seizures in the maximal electroshock seizures (MES) test (left panel). In the corneal electrical stimulation (CES) seizure test (right panel), NLX-101 reduced seizure occurrence in only 1 out of 4 mice at the highest dose tested, and at only one time point (30 min post injection). The minimal activity of NLX-101 in the MES and CES tests suggest that it does not possess anti-seizure activity (Figure 1 ).
  • NLX-101 dose-dependently reduced the percentage of FMR1 knock-out mice displaying tonic-clonic seizures, with significant effects at 1.8 and 2.4 mg/kg (left panels).
  • NLX-101 also dose-dependently reduced the number of FMR1 knock-out mice that died, with significant effects at doses of 1 .2, 1 .8 and 2.4 mg/kg (right panels).
  • Each experimental groups consisted of 14 or 16 mice (half of which were males, half were females).

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Abstract

La présente invention concerne le traitement et la prévention de maladies associées à un risque accru de mort subite inattendue en épilepsie, telles que le syndrome de l'X fragile, par l'administration d'un agoniste sélectif du récepteur de 5-HT1A.
PCT/EP2023/051732 2022-01-26 2023-01-25 Utilisation d'agonistes du récepteur de la sérotonine 5-ht1a pour traiter des maladies associées à la mort subite inattendue en épilepsie WO2023144166A1 (fr)

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US63/303,372 2022-01-26
US17/586,477 US11974992B2 (en) 2022-01-26 2022-01-27 Use of serotonin 5-HT1A receptor agonists to treat diseases associated with sudden unexpected death in epilepsy
US17/586,477 2022-01-27

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003106449A1 (fr) 2002-06-18 2003-12-24 Pierre Fabre Medicament Nouveaux derives d'aryl-{4-halogeno-4-[heteroaryl-methylamino)-methyl]-piperidin-1-yl}-methanone, leur procede de preparation et leur utilisation a titre de medicaments
WO2016138138A1 (fr) 2015-02-25 2016-09-01 The Regents Of The University Of California Agonistes de récepteur 5ht pour le traitement de troubles

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003106449A1 (fr) 2002-06-18 2003-12-24 Pierre Fabre Medicament Nouveaux derives d'aryl-{4-halogeno-4-[heteroaryl-methylamino)-methyl]-piperidin-1-yl}-methanone, leur procede de preparation et leur utilisation a titre de medicaments
WO2016138138A1 (fr) 2015-02-25 2016-09-01 The Regents Of The University Of California Agonistes de récepteur 5ht pour le traitement de troubles

Non-Patent Citations (18)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2000, LIPPINCOTT WILLIAMS & WILKINS
ARMSTRONG JESSICA L. ET AL: "( S )-5-(2'-Fluorophenyl)- N , N -dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine, a Serotonin Receptor Modulator, Possesses Anticonvulsant, Prosocial, and Anxiolytic-like Properties in an Fmr1 Knockout Mouse Model of Fragile X Syndrome and Autism Spectrum Disorder", ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE, vol. 3, no. 3, 21 February 2020 (2020-02-21), pages 509 - 523, XP093038570, ISSN: 2575-9108, DOI: 10.1021/acsptsci.9b00101 *
BARTON MEKLEIN BDWOLF HHWHITE HS: "Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy", EPILEPSY RES, vol. 47, 2001, pages 217 - 27, XP055090437, DOI: 10.1016/S0920-1211(01)00302-3
COSTA ET AL., BIOL PSYCHIATRY, vol. 72, no. 11, 18 July 2012 (2012-07-18), pages 924 - 33
FUJII ET AL., YAKUBUTSU SEISHIN KODO, vol. 11, no. 1, February 1991 (1991-02-01), pages 29 - 35
HANSEN WANG ET AL: "Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndromes", FRONTIERS IN CELLULAR NEUROSCIENCE, vol. 9, 26 February 2015 (2015-02-26), XP055644251, DOI: 10.3389/fncel.2015.00055 *
LEVITT ERICA S. ET AL: "A selective 5-HT 1a receptor agonist improves respiration in a mouse model of Rett syndrome", JOURNAL OF APPLIED PHYSIOLOGY, vol. 115, no. 11, 1 December 2013 (2013-12-01), US, pages 1626 - 1633, XP093038785, ISSN: 8750-7587, DOI: 10.1152/japplphysiol.00889.2013 *
LEVITT ET AL., J.APPLI. PHYSIOL., vol. 115, 2013, pages 1626 - 1633
LLADΔ-PELFORT ET AL., J PHARMACOL, vol. 160, no. 8, August 2010 (2010-08-01), pages 1929 - 40
MCKEAN ET AL., PHARMACOTHERAPY, vol. 35, no. 3, March 2015 (2015-03-01), pages e6 - 8
PETRUCCI ALEXANDRA N ET AL: "Serotonin and sudden unexpected death in epilepsy", EXPERIMENTAL NEUROLOGY, ELSEVIER, AMSTERDAM, NL, vol. 325, 19 December 2019 (2019-12-19), XP085979883, ISSN: 0014-4886, [retrieved on 20191219], DOI: 10.1016/J.EXPNEUROL.2019.113145 *
PHARMACOL REP, vol. 57, no. 3, May 2005 (2005-05-01), pages 336 - 44
SINGH JATINDER ET AL: "Autonomic Characteristics of Sudden Unexpected Death in Epilepsy in Children-A Systematic Review of Studies and Their Relevance to the Management of Epilepsy in Rett Syndrome", FRONTIERS IN NEUROLOGY, vol. 11, 5 February 2021 (2021-02-05), XP093039038, DOI: 10.3389/fneur.2020.632510 *
SNIECIKOWSKA ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 62, 2019, pages 2750 - 2771
SRINIVASAN TUPAL ET AL: "Fenfluramine, a serotonin-releasing drug, prevents seizure-induced respiratory arrest and is anticonvulsant in the DBA/1 mouse model of SUDEP", EPILEPSIA, RAVEN PRESS LTD, NEW YORK , US, vol. 60, no. 3, 4 February 2019 (2019-02-04), pages 485 - 494, XP071214320, ISSN: 0013-9580, DOI: 10.1111/EPI.14658 *
TAO X. ET AL: "Acute and Repeated Administration of NLX-101, a Selective Serotonin-1A Receptor Biased Agonist, Reduces Audiogenic Seizures in Developing Fmr1 Knockout Mice", NEUROSCIENCE, vol. 509, 1 January 2023 (2023-01-01), US, pages 113 - 124, XP093038584, ISSN: 0306-4522, DOI: 10.1016/j.neuroscience.2022.11.014 *
YANG ET AL., NEUROSCI BULL, vol. 30, no. 3, January 2014 (2014-01-01), pages 401 - 8
YANG YI ET AL: "Serotonin 1A receptor inhibits the status epilepticus induced by lithium-pilocarpine in rats", NEUROSCIENCE BULLETIN, SHANGHAI INSTITUTES FOR BIOLOGICAL SCIENCES, CHINESE ACADEMY OF SCIENCES, HEIDELBERG, vol. 30, no. 3, 15 January 2014 (2014-01-15), pages 401 - 408, XP035317121, ISSN: 1673-7067, [retrieved on 20140115], DOI: 10.1007/S12264-013-1396-X *

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