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1. (WO2019002548) TREATING MIGRAINE BY AGONISING TREK1, TREK2 OR HETEROMERS INCLUDING THEM
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Pub. No.: WO/2019/002548 International Application No.: PCT/EP2018/067581
Publication Date: 03.01.2019 International Filing Date: 29.06.2018
IPC:
A61K 31/404 (2006.01) ,A61K 31/4045 (2006.01) ,A61K 31/405 (2006.01) ,A61K 31/5415 (2006.01)
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
33
Heterocyclic compounds
395
having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
40
having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
403
condensed with carbocyclic rings, e.g. carbazole
404
Indoles, e.g. pindolol
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
33
Heterocyclic compounds
395
having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
40
having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
403
condensed with carbocyclic rings, e.g. carbazole
404
Indoles, e.g. pindolol
4045
Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
33
Heterocyclic compounds
395
having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
40
having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
403
condensed with carbocyclic rings, e.g. carbazole
404
Indoles, e.g. pindolol
405
Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
33
Heterocyclic compounds
395
having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
54
having six-membered rings with at least one nitrogen and at least one sulfur as the ring hetero atoms, e.g. sulthiame
5415
ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
Applicants:
INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE) [FR/FR]; 101, rue de Tolbiac 75013 Paris, FR
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS) [FR/FR]; 3, Rue Michel Ange 75016 Paris, FR
UNIVERSITE NICE SOPHIA ANTIPOLIS [FR/FR]; Grand Château Parc Valrose, 28 avenue Valrose 06103 Nice, FR
Inventors:
SANDOZ, Guillaume; FR
ROYAL, Perrine; FR
BARON, Anne; FR
LESAGE, Florian; FR
VERKEST, Clément; FR
Agent:
INSERM TRANSFERT; 7 rue Watt 75013 Paris, FR
Priority Data:
17305813.229.06.2017EP
Title (EN) TREATING MIGRAINE BY AGONISING TREK1, TREK2 OR HETEROMERS INCLUDING THEM
(FR) TRAITEMENT DE LA MIGRAINE PAR TREK1, TREK2 D'AGONISATION OU HÉTÉROMÈRES LES COMPRENANT
Abstract:
(EN) Inventors have found that the MT mutation puts an alternative start codon in frame which leads to the translation of a second TRESK fragment. Surprisingly, the 2 gene products, termed MT1 and MT2, have differential dominant negative effects: MT1 targets TRESK while MT2 targets TREK1 and TREK2, members of another subfamily of K2P channels. Furthermore, they have shown that by co-assembling with and inhibiting TREK1 and TREK2, MT2 increases TG excitability. This resolves the contradictory lack of effects of TRESK-C110R which targets only TRESK and not TREK1 or TREK2. Together their results demonstrate that alternative translation initiation is a mechanism initiated by the TRESK-MT mutation which leads to two protein fragments with dominant negative effects on distinct channel targets. The present invention relates to a method for treating migraine in a subject in need thereof comprising a step of administering the subject with a therapeutically effective amount of agonists of: TREK1, TREK2, TRESK-TREK1, TRESK-TREK2 or TREK1-TREK2.
(FR) Les inventeurs ont découvert que la mutation MT met en place un autre codon de départ dans le cadre qui mène à la traduction d'un second fragment TRESK. De manière surprenante, les 2 produits géniques, appelés MT1 et MT2, ont des effets négatifs dominants différentiels : MT1 cibles TRESK tandis que MT2 cibles TREK1 et TREK2, des membres d'une autre sous-famille de canaux K2P. En outre, ils ont montré que par co-assemblage avec et inhibition de TREK1 et TREK2, MT2 augmente l'excitabilité TG. Ceci permet de résoudre le manque d'effets contradictoires de TRESK-C110R qui cible uniquement TRESK et non TREK1 ou TREK2. Les résultats démontrent que l'initiation de traduction alternative est un mécanisme initié par la mutation TRESK-MT qui conduit à deux fragments de protéine ayant des effets négatifs dominants sur des cibles de canal distinctes. La présente invention concerne une méthode de traitement de la migraine chez un sujet en ayant besoin, comprenant une étape d'administration audit sujet d'une quantité thérapeutiquement efficace d'agonistes de : TREK1, TREK2, TRESK-TREK1, TRESK-TREK2 ou TREK1-TREK2.
Designated States: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW
African Regional Intellectual Property Organization (ARIPO) (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW)
Eurasian Patent Office (AM, AZ, BY, KG, KZ, RU, TJ, TM)
European Patent Office (EPO) (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR)
African Intellectual Property Organization (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG)
Publication Language: English (EN)
Filing Language: English (EN)