DK3074032T3 - Fedtsyrederivater af dimeriske PSD-95-inhibitorer - Google Patents

Fedtsyrederivater af dimeriske PSD-95-inhibitorer Download PDF

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DK3074032T3
DK3074032T3 DK14821058.6T DK14821058T DK3074032T3 DK 3074032 T3 DK3074032 T3 DK 3074032T3 DK 14821058 T DK14821058 T DK 14821058T DK 3074032 T3 DK3074032 T3 DK 3074032T3
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Denmark
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acid
amino acid
dimeric ligand
linker
integer
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DK14821058.6T
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Anders Bach
Klaus Bertram Nissen
Kristian Strømgaard
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Univ Copenhagen
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • 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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pain & Pain Management (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Claims (15)

1. Dimerisk ligand af PSD-95 omfattende et første peptid (Pi) og et andet peptid (P2), hvor Pi og P2 individuelt omfatter mindst to proteinogene eller ikke-proteinogene aminosyre-rester, både Pi og P2 er konjugeret til en første linker Li via deres N-terminaler, Li omfatter polyethylenglycol (PEG), hvor mindst ét oxygenatom af PEG er substitueret med et nitrogenatom for at give Λ/PEG, en albuminbindende del er bundet til nitrogenatomet i Λ/PEG ved hjælp af en amidbinding eller via en valgfri linker L2, hvor L2 omfatter et nitrogenatom, den albuminbindende del er en fedtsyre (FA), og hvor den dimeriske ligand har den generiske struktur med formel (II), hvor L2 er valgfrit:
Formel (Ih eller et farmaceutisk acceptabelt salt eller prodrug deraf.
2. Dimerisk ligand ifølge et hvilket som helst af de foregående krav, hvor den anden linker L2 omfatter en eller flere dele valgt fra gruppen bestående af γ-Glu, Y-smørsyre (GABA), 5-aminovalerinsyre (5-Ava), proteinogene aminosyrer, ikke-proteinogene aminosyrer og en hvilken som helst dimerisk ligand med den almene formel H2N-[Qj-COOH, hvor Q er et hvilket som helst egnet atom eller atomer.
3. Dimerisk ligand ifølge et hvilket som helst af de foregående krav, hvor den dimeriske ligand har den generiske struktur med formel (III) eller (IV):
hvor Ri og R2 individuelt er valgt fra gruppen bestående af H og COOH, n er et helt tal 0 til 48, m er et helt tal 1 til 48, p er et helt tal 0 til 28, q er et helt tal 0 til 28, i er et helt tal 0 til 12, j er et helt tal 0 til 12 Pi og P2 individuelt er valgt blandt peptider omfattende mindst to proteinogene eller ikke-proteinogene aminosyrerester.
4. Dimerisk ligand ifølge et hvilket som helst af de foregående krav, hvor fedtsyren er en C4-C22 fedtsyre.
5. Dimerisk ligand ifølge et hvilket som helst af de foregående krav, hvor fedtsyren er valgt fra gruppen bestående af caprylsyre, caprinsyre, laurinsyre, myristinsyre, pal-mitinsyre, stearinsyre, arachinsyre, behensyre, lignocerinsyre, cerotinsyre, myristolein-syre, palmitoleinsyre, sapiensyre, oliesyre, elaidinsyre, vaccensyre, linoleinsyre, lino-elaidinsyre, α-linolensyre, arachidonsyre, eicosapentaensyre, erucasyre og docosa-hexaensyre.
6. Dimerisk ligand ifølge et hvilket som helst af de foregående krav, hvor Pi omfatter aminosyresekvensen X4X3X2X1 (SEQ ID NO: 1), og P2 omfatter aminosyresekvensen Z4Z3Z2Z1 (SEQ ID NO: 2), hvor Xi og/eller Z1 er en aminosyrerest valgt blandt I, L og V, X2 og/eller Z2 er en aminosyrerest valgt blandt A, D, E, Q, N, S, V, /V-Me-A, N-Me-D, /V-Me-E, /V-Me-Q, /V-Me-N, /V-Me-S og N-Me-V, X3 og/eller Z3 er en aminosyrerest valgt blandt S og T, X4 og/eller Z4 er en aminosyrerest valgt blandt E, Q, A, N og S, hvorXi og Z1 begge individuelt repræsenterer den ultimative C-terminale aminosyrerest omfattende en fri carboxylsyre.
7. Dimerisk ligand ifølge et hvilket som helst af de foregående krav, hvor den dimeriske ligand har den generiske struktur med formel (V) eller (VI):
hvor Ri og R2 individuelt er valgt fra gruppen bestående af H og COOH, n er et helt tal 0 til 48, m er et helt tal 1 til 48, p er et helt tal 0 til 28, q er et helt tal 0 til 28, i er et helt tal 0 til 12, j er et helt tal 0 til 12 X5 og/eller Z5 er en valgfri proteinogen eller en ikke-proteinogen aminosyrerest, et peptid eller et polypeptid, X4 og/eller Z4 er en aminosyrerest valgt blandt E, Q, A, N og S, X3 og/eller Z3 er en aminosyrerest valgt blandt S og T,
X2 og/eller Z2 er en aminosyrerest valgt blandt A, D, E, Q, N, S, V, /V-Me-A, N-Me-D, /V-Me-E, /V-Me-Q, /V-Me-N, /V-Me-S og /V-Me-V, Xi og/eller Z1 er en aminosyrerest valgt blandt I, L og V.
8. Dimerisk ligand ifølge et hvilket som helst af de foregående krav, hvor X5 er en aminosyrerest valgt fra gruppen bestående af I, A, L og V.
9. Dimerisk ligand ifølge et hvilket som helst af de foregående krav, hvor den dimeriske ligand er valgt fra gruppen bestående af: a) KBN41 (5) derivat
10. Dimerisk ligand ifølge et hvilket som helst af de foregående krav, hvor den dimeri-ske ligand er valgt fra gruppen bestående af:
11. Dimerisk ligand ifølge et hvilket som helst af de foregående krav, hvor den dimeri-ske ligand er valgt fra gruppen bestående af:
12. Dimerisk ligand ifølge et hvilket som helst af de foregående krav til anvendelse som lægemiddel.
13. Dimerisk ligand ifølge et hvilket som helst af kravene 1 til 13 til anvendelse til behandling eller profylakse af smerte og/eller en excitotoksisk-relateret sygdom.
14. Dimerisk ligand ifølge krav 13, hvor sygdommen er iskæmisk eller traumatisk skade på / i / af CNS.
15. Fremgangsmåde til fremstilling af den dimeriske ligand ifølge et hvilket som helst af kravene 1 til 14, hvilken fremgangsmåde omfatter trinnene: a) fremstilling af en Ns-A/PEG disyrelinker, b) fremstilling af et peptid under anvendelse af Fmoc-baseret fastfasepeptidsyn-tese, c) dimerisering af peptidet med Ns-A/PEG disyrelinkeren og d) kobling af en fedtsyre til linkeren
DK14821058.6T 2013-12-01 2014-11-26 Fedtsyrederivater af dimeriske PSD-95-inhibitorer DK3074032T3 (da)

Applications Claiming Priority (2)

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DKPA201370735 2013-12-01
PCT/DK2014/050402 WO2015078477A1 (en) 2013-12-01 2014-11-26 Fatty acid derivatives of dimeric inhibitors of psd-95

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US (1) US20160303245A1 (da)
EP (1) EP3074032B1 (da)
JP (1) JP6633523B2 (da)
KR (1) KR20160091980A (da)
CN (1) CN105828832A (da)
AU (1) AU2014356912B2 (da)
BR (1) BR112016012391A2 (da)
CA (1) CA2931694C (da)
DK (1) DK3074032T3 (da)
ES (1) ES2716890T3 (da)
IL (1) IL245904A (da)
MX (1) MX2016006966A (da)
PL (1) PL3074032T3 (da)
WO (1) WO2015078477A1 (da)

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HUE034308T2 (en) 2013-03-21 2018-02-28 Sanofi Aventis Deutschland Preparation of hydantoin-containing peptide products
CN105102427B (zh) 2013-03-21 2018-09-07 赛诺菲-安万特德国有限公司 含有环状酰亚胺的肽产物的合成
CN107226840A (zh) * 2017-05-04 2017-10-03 西安交通大学 一种细胞穿膜肽透皮吸收促进剂及其制备方法和应用
CN109030662B (zh) * 2018-09-14 2021-04-13 广西医科大学第一附属医院 检测致痫大鼠海马组织谷氨酸及r-氨基丁酸含量的方法
WO2021176094A1 (en) 2020-03-06 2021-09-10 University Of Copenhagen Lipid conjugated peptide inhibitors of pick1
AU2022206444A1 (en) 2021-01-08 2023-07-20 Nono Inc. Plasmin-resistant peptides for improved therapeutic index
AU2024208633A1 (en) 2023-01-09 2025-07-24 Beijing Tuo Jie Biopharmaceutical Co. Ltd. Neuroprotective psd-95 polypeptide inhibitor and use thereof
CN119569824A (zh) * 2023-09-07 2025-03-07 湖南中晟全肽生物科技股份有限公司 作为神经保护剂的药用化合物及其应用

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GB9215780D0 (en) * 1992-07-24 1992-09-09 Univ London Pharmacy Peptide compounds
WO2010004003A2 (en) 2008-07-09 2010-01-14 University Of Copenhagen Modified peptides as potent inhibitors of the psd-95/nmda receptor interaction
PL2707014T3 (pl) 2011-05-13 2015-12-31 Koebenhavns Univ University Of Copenhagen Dimeryczne inhibitory PSD-95 o wysokim powinowactwie i ich zastosowanie w terapii niedokrwiennego uszkodzenia mózgu oraz leczeniu bólu
US9139615B2 (en) * 2011-05-13 2015-09-22 University Of Copenhagen High-affinity, dimeric inhibitors of PSD-95 as efficient neuroprotectants against ischemic brain damage and for treatment of pain
WO2013088382A1 (en) * 2011-12-13 2013-06-20 Nono Inc. Therapy for subarachnoid hemorrhage and ischemia
WO2013151538A1 (en) * 2012-04-03 2013-10-10 Empire Technology Development Llc Fluorescent labeling of living cells

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IL245904A (en) 2017-10-31
AU2014356912A1 (en) 2016-06-09
BR112016012391A2 (pt) 2017-09-26
ES2716890T3 (es) 2019-06-17
AU2014356912B2 (en) 2019-08-01
KR20160091980A (ko) 2016-08-03
MX2016006966A (es) 2017-01-19
CN105828832A (zh) 2016-08-03
CA2931694A1 (en) 2015-06-04
CA2931694C (en) 2020-12-01
IL245904A0 (en) 2016-07-31
PL3074032T3 (pl) 2019-06-28
EP3074032B1 (en) 2018-12-26
JP2017501132A (ja) 2017-01-12
US20160303245A1 (en) 2016-10-20
EP3074032A1 (en) 2016-10-05
JP6633523B2 (ja) 2020-01-22
WO2015078477A1 (en) 2015-06-04

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