CN105412134A - Anti-inflammation application of guaiane type sesquiterpenes activin receptor-like kinase 5 inhibitor - Google Patents

Anti-inflammation application of guaiane type sesquiterpenes activin receptor-like kinase 5 inhibitor Download PDF

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Publication number
CN105412134A
CN105412134A CN201510828139.XA CN201510828139A CN105412134A CN 105412134 A CN105412134 A CN 105412134A CN 201510828139 A CN201510828139 A CN 201510828139A CN 105412134 A CN105412134 A CN 105412134A
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China
Prior art keywords
activin receptor
kinase
antagonist
inhibitor
inflammation
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CN201510828139.XA
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Chinese (zh)
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严明
汪豪
俞沁玮
高鹏
张陆勇
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China Pharmaceutical University
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China Pharmaceutical University
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to an activin receptor-like kinase 5 antagonist in the formula (I) and salts acceptable pharmaceutically. The compounds can effectively antagonize activin receptor-like kinase 5 and effectively have the anti-inflammation function.

Description

The antiphlogistic use of one class guainane type sesquiterpene activin element receptor-like kinase enzyme 5 inhibitor
Technical field
The present invention relates to the antiphlogistic use of class guaiaci lignum alkane type sesquiterpene activin receptor sample kinases 5 antagonist.
Background technology
Transforming growth factor-β (Transforminggrowthfactor-β, TGF-β) be the multi-functional cytokine of a class, belong to a type cytokines superfamily, cytokine can the increment of cell, differentiation, attachment, migration and apoptosis, there is physiological action widely.Transforming growth factor-β (transforminggrowthfactor β, TGF-β) be found as a kind of somatomedin in oncobiology field at first, found that it take part in much important physiology and pathological process afterwards, all hypotypes of TGF-beta receptor have now become the focus of many scholar's research.TGF-β I receptor, also known as activin receptor sample kinases (Activinreceptor-likekinases, ALKs).So far, in mammal, find that there is 7 kinds of TGF-β I receptor hypotype (i.e. ALK-1 to ALK-7) altogether.TGF-β activates Smad albumen by transmembrane serine/threonine kinases receptors and plays a role.The conduction of the signal of TGF-beta superfamily needs the combined effect of TypeI (or activinlikekinase, ALK) receptor and TypeII receptor.
Inflammation is the biological tissue with vascular system is inflammation to the defense reaction that damage factor occurs.Vascular reaction is the key link of inflammatory process.Inflammation is a clinical common pathological process, can be born in the tissue at each position of body and each organ.Acute inflammation have at ordinary times red, swollen, hot, bitterly, function the change such as to hide, with often with general reactions such as heating, leukocytosiss.That body is for a kind of defense reaction stimulated.
Up-to-date research shows, the disease height correlations such as the fibrosis lesion of the exception of transforming growth factor β signal and various cancer, important organ, and the important node TypeI receptor (ALK-5) in transforming growth factor β signal path is the ideal targets of these diseases for the treatment of.TGF-β is a cytokine with multi-biological effect, and it is in adjustment cell proliferation and differentiation, and fetal development, the aspect such as repair in trauma and inflammatory reaction plays a significant role.So it is significant to treatment inflammation to set up ALK-5 receptor antagonist screening model.
Summary of the invention
In order to develop activin receptor sample kinases 5 receptor antagonist thus find new drug candidate for the treatment of inflammation, the present invention is at employing activin receptor sample kinases 5 antagonist high flux screening model, lead compound is found by functional authorization, find class guaiaci lignum alkane type sesquiterpene activin receptor sample kinases 5 antagonist, for the exploitation of novel anti-inflammatory agent provides lead compound.The exploitation that the present invention can be this type of clinical anti-inflammatory treatment medicine provides lead compound, for novel anti-inflammatory drug exploitation is given a clue and experimental basis.
Technical scheme of the present invention is: set up activin receptor sample kinases 5 antagonist high flux screening model, primary dcreening operation, and multiple sieve, Structure-activity analysis, obtains the drug candidate that a class has antiinflammatory action.Concrete steps are as follows:
Step one: antagonist is set up and the checking of positive medicine.
Step 2: adopt and test the optimal detection condition determined carries out activin receptor sample kinases 5 body antagonist high flux screening to compound, obtain the compound of pronounced amount effect relationship.
Accompanying drawing illustrates:
Fig. 1: antagonist control amount effect curve
Fig. 2: lead compound 1 amount effect curve
Fig. 3: lead compound 2 amount effect curve
Detailed description of the invention
Below in conjunction with accompanying drawing, the specific embodiment of the present invention is described:
1. antagonist is set up and positive drug checking, determines the EC of antagonist 50:
1) experiment material
ALK5, KinaseBufferA, KinaseTracer178, LanthaScreen tMeu-anti-GSTAntibody (Invitrogen, USA), Dasatinib, 384 holes black microwell plate (Corning, USA) rifle head (Axygen, USA)
2) experimental procedure
The positive drug (Dasatinib) of preparation variable concentrations, every hole adds 5 μ l.The mixed solution (3 times of final concentrations) of preparation kinases and antibody, every hole adds 5 μ l.Prepare tracer Tracer concentration close to Kd, every hole adds 5 μ l.Detect after room temperature reaction 1h and calculate suppression ratio mapping, experimental result is shown in Fig. 1.
2. adopt above-mentioned Model Condition to carry out primary dcreening operation and multiple sieve to activin receptor sample kinases 5 antagonist.Process data, calculate institute SCREENED COMPOUND IC 50.Carry out Structure-activity analysis to the compounds effective filtered out, lead compound experimental result is shown in Fig. 2, Fig. 3.
Activin receptor sample kinases 5 screening active ingredients experimental result
Screening activin receptor sample kinases 5 antagonist obtained is guaiaci lignum alkane type sesquiterpene compound, its general structure and IC 50as follows:
Wherein
R 1for OH or O-β-D-Glc;
R 2for OH or H;
R 3for α-H, β-CH 3or=CH 2.
Preferred structural formula:
Lead compound 1 (AF-7): R 1=O-β-D-Glc, R 2=OH; R 3=α-H, β-CH 3;
Chemical name: 8 Alpha-hydroxy-11 α H-11,13-dihydro-zaluzanin C-3-O-β-D-Glucose glycosides
(8α-hydroxy-11αH-11，13-dihydro-zaluzaninC-3-O-β-D-glucopyranoside)。
Lead compound 2 (AF-4): R 1=O-β-D-Glc, R 2=H, R 3=CH 2;
Chemical name: zaluzanin C-3-O-β-D-Glucose glycosides
(ZaluzaninC-3-O-β-D-glucopyranoside)。
Lead compound is to activin receptor sample kinases 5 antagonistic activity:

Claims (2)

1. the compound of the formula (I) that claim 1 is claimed or its pharmaceutically acceptable salt in the purposes of activin receptor sample kinases 5 antagonist.
Wherein
R 1for OH or O-β-D-Glc;
R 2for OH or H;
R 3for α-H, β-CH 3or=CH 2.
Formula (I).
2. according to the purposes of claim 1, as activin receptor sample kinases 5 antagonist, for the preparation of the purposes of anti-inflammatory agent.
CN201510828139.XA 2015-11-20 2015-11-20 Anti-inflammation application of guaiane type sesquiterpenes activin receptor-like kinase 5 inhibitor Pending CN105412134A (en)

Priority Applications (1)

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CN201510828139.XA CN105412134A (en) 2015-11-20 2015-11-20 Anti-inflammation application of guaiane type sesquiterpenes activin receptor-like kinase 5 inhibitor

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113347985A (en) * 2019-01-30 2021-09-03 帝斯曼知识产权资产管理有限公司 Use of a fraction of laurel extract for combating air pollution related diseases
CN113788840A (en) * 2021-09-15 2021-12-14 中国科学院昆明植物研究所 Guaiane sesquiterpene polymer and its medicine, preparation method and application

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101279964A (en) * 2008-02-29 2008-10-08 中国药科大学 Guaiane type sesquiterpenes, preparation and medical use thereof
CN101347482A (en) * 2008-03-07 2009-01-21 上海中创医药科技有限公司 Ainsliaea fragrans extract and active component thereof as well as their quality control method

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101279964A (en) * 2008-02-29 2008-10-08 中国药科大学 Guaiane type sesquiterpenes, preparation and medical use thereof
CN101347482A (en) * 2008-03-07 2009-01-21 上海中创医药科技有限公司 Ainsliaea fragrans extract and active component thereof as well as their quality control method

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
RENE DOS REIS PIORNEDO等: "Anti-inflammaory activity of extracts and 11,13-dihydrozaluzanin C from Gochnatia polymorpha ssp. floccosa trunk bark in mice", 《JOURNAL OF ETHNOPHARMACOLOGY》 *
刘戈等: "菊科植物杏香兔耳风的化学成分", 《中国天然药物》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113347985A (en) * 2019-01-30 2021-09-03 帝斯曼知识产权资产管理有限公司 Use of a fraction of laurel extract for combating air pollution related diseases
CN113788840A (en) * 2021-09-15 2021-12-14 中国科学院昆明植物研究所 Guaiane sesquiterpene polymer and its medicine, preparation method and application
CN113788840B (en) * 2021-09-15 2023-08-11 中国科学院昆明植物研究所 Guaiane sesquiterpene polymer and medicine thereof, and preparation method and application thereof

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