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ES2555252T3 - Ligandos de Na/K-ATPasa, antagonistas de ouabaína, ensayos y uso de los mismos - Google Patents

Ligandos de Na/K-ATPasa, antagonistas de ouabaína, ensayos y uso de los mismos Download PDF

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Publication number
ES2555252T3
ES2555252T3 ES10817681.9T ES10817681T ES2555252T3 ES 2555252 T3 ES2555252 T3 ES 2555252T3 ES 10817681 T ES10817681 T ES 10817681T ES 2555252 T3 ES2555252 T3 ES 2555252T3
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ES
Spain
Prior art keywords
och3
assays
atpase
ouabain
ligands
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Active
Application number
ES10817681.9T
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English (en)
Inventor
Zi-Jian Xie
Joseph I. Shapiro
Shuyi Si
Zhongbing Zhang
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University of Toledo
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University of Toledo
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

Un ligando de Na/K-ATPasa, que comprende al menos un derivado de hidroxil xantona que tiene la estructura:**Fórmula** en la que R1 >= R2 >= R6 >= R7 >= R8 >= H, y R3 >= R4 >= R5 >= OH, concretamente 3,4,5-trihidroxixantona (MB5); o R1 >= R2 >= R7 >= R8 >= H, y R3 >= R4 >= R5 >= R6 >= OH, concretamente 3,4,5,6-tetrahidroxixantona (MB7), para su uso en el tratamiento de hipertrofia cardiaca, fibrosis tisular y/o insuficiencia cardiaca congestiva.

Description

imagen1
imagen2
imagen3
imagen4
2006BC9
4-Epitetraciclina imagen5
2018BF7
Miricetina imagen6
2021BG2
Bromuro de domifeno imagen7
2035BD1
Resibufogenina imagen8
2035BA5
Cinobufagina imagen9
2036BF1
Oligomicina imagen10
MB1
1,3-Dihidroxixantona imagen11
MB2
3,4-Dihidroxixantona imagen12
MB3
1,3,5-Trihidroxixantona imagen13
MB5
3,4,5-Trihidroxixantona imagen14
MB6
1,3,5,6-Tetrahidroxixantona imagen15
MB7
3,4,5,6-Tetrahidroxixantona imagen16
Identificación de hidroxixantonas como una nueva clase de ligandos de Na/K-ATPasa: entre los quince impactos positivos, numerosos son compuestos polifenólicos incluyendo seis derivados de hidroxil xantona (MB1 a MB7) (Tabla 1). Estructuralmente, son similares a compuestos polifenólicos bien caracterizados tales como quercetina (Figura 1B). Los inventores del presente documento determinaron a continuación las propiedades inhibidoras de estas hidroxixantonas. Debido a que MB7 fue el inhibidor más potente de este grupo (Tabla II posterior), se usó en los siguientes estudios.
Tabla II Relación de estructura y actividad de derivados de xantona
n.º de muestra
Posición del sustituyente CI50 (µM)
R1
R2 R3 R4 R5 R6 R7 R8
MB1
OH H OH H H H H H > 100
MB2
H H OH OH H H H H > 100
MB3
OH H OH H OH H H H 65
MB5
H H OH OH OH H H H 10
MB 6
OH H OH H OH OH H H 60
MB7
H H OH OH OH OH H H 5
MB8
H H OCH3 OCH3 H OCH3 H H > 100
2027BA1
OH H OCH3 H H H OH OCH3 > 100
2027BA2
OH H OCH3 H H H OCH3 OH > 100
C-017
OCH3 OCH3 OCH3 H H H OCH3 H > 100
10 En los experimentos representados en la Figura 1A, las curvas de respuesta a dosis de MB7 se compararon con la ouabaína. Al igual que la ouabaína, MB7 exhibió una inhibición dependiente de dosis de Na/K-ATPasa. El valor de
6
imagen17
imagen18
imagen19
imagen20

Claims (1)

  1. imagen1
    imagen2
ES10817681.9T 2009-09-16 2010-09-09 Ligandos de Na/K-ATPasa, antagonistas de ouabaína, ensayos y uso de los mismos Active ES2555252T3 (es)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US24303609P 2009-09-16 2009-09-16
US243036P 2009-09-16
PCT/US2010/048227 WO2011034772A1 (en) 2009-09-16 2010-09-09 Na/k-atpase ligands, ouabain antagonists, assays and uses thereof

Publications (1)

Publication Number Publication Date
ES2555252T3 true ES2555252T3 (es) 2015-12-30

Family

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Country Status (7)

Country Link
US (3) US20120302630A1 (es)
EP (1) EP2477494B1 (es)
JP (1) JP5764130B2 (es)
CN (1) CN102573469B (es)
CA (1) CA2774486C (es)
ES (1) ES2555252T3 (es)
WO (1) WO2011034772A1 (es)

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CN103463621B (zh) 2006-10-31 2016-01-06 托莱多大学 Src和Src家族激酶的Na+/K+-ATP酶特异性肽抑制剂/激活剂
WO2011034772A1 (en) 2009-09-16 2011-03-24 The University Of Toledo Na/k-atpase ligands, ouabain antagonists, assays and uses thereof
WO2011088210A1 (en) 2010-01-13 2011-07-21 The University Of Toledo Materials and methods related to sodium/potassium adenosine triphosphatase and src
CN104968799A (zh) * 2012-05-08 2015-10-07 托莱多大学 使用受体Na/K-ATPase/Src复合物进行的测定法和基于细胞的测试及其用途
US20150265675A1 (en) * 2012-10-17 2015-09-24 Darwin J. Prockop Treatment of Brain Injury or Trauma with TSG-6 Protein
CN104557841B (zh) * 2014-11-27 2017-05-24 中国科学院南海海洋研究所 两个色酮类化合物及其制备方法和在制备抗肿瘤药物中的应用
PT3250218T (pt) 2015-01-30 2021-05-14 Marshall Univ Research Corporation Péptido natkide para o tratamento da obesidade
JP7549345B2 (ja) * 2019-02-08 2024-09-11 学校法人近畿大学 悪性腫瘍疾患の改善用組成物
WO2021072083A1 (en) * 2019-10-08 2021-04-15 Marshall University Research Corporation Na/K-ATPase LIGANDS AND USE THEREOF FOR TREATMENT OF CANCER

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Publication number Publication date
CA2774486C (en) 2019-06-04
EP2477494A1 (en) 2012-07-25
US20150272923A1 (en) 2015-10-01
US20120302630A1 (en) 2012-11-29
CA2774486A1 (en) 2011-03-24
EP2477494A4 (en) 2013-04-10
US20140031419A1 (en) 2014-01-30
CN102573469B (zh) 2015-02-25
JP5764130B2 (ja) 2015-08-12
WO2011034772A1 (en) 2011-03-24
EP2477494B1 (en) 2015-11-11
JP2013505241A (ja) 2013-02-14
US9114126B2 (en) 2015-08-25
CN102573469A (zh) 2012-07-11

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