WO2005092328A1 - Fxr活性化化合物 - Google Patents
Fxr活性化化合物 Download PDFInfo
- Publication number
- WO2005092328A1 WO2005092328A1 PCT/JP2005/003600 JP2005003600W WO2005092328A1 WO 2005092328 A1 WO2005092328 A1 WO 2005092328A1 JP 2005003600 W JP2005003600 W JP 2005003600W WO 2005092328 A1 WO2005092328 A1 WO 2005092328A1
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- Prior art keywords
- fxr
- group
- formula
- cholesterol
- formulas
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- 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
Definitions
- the present invention relates to a FXR (farnesoid X receptor) transcriptional activity regulator useful as a preventive and therapeutic agent for hyperlipidemia and a preventive and therapeutic agent for intrahepatic cholestasis.
- FXR farnesoid X receptor
- Hyperlipidemia causes an excess of lipids in the blood due to hereditary or inadequate diet and lack of exercise, causing arteriosclerosis to lead to various adult diseases such as ischemic heart disease.
- nuclear receptors are activated by the binding of ligands, are transcription factors that control the expression of target genes, and play an important role in various physiological phenomena.
- FXR ligand cadenodeoxycholic acid CDCA
- CDCA enhances the transcriptional activity of FXR.
- Bile acids are synthesized from cholesterol, and this conversion is suppressed by the final product, bile acids.
- FXR which is activated by bile acids, controls this feedback by suppressing the gene expression of cholesterol 7a-hydroxylase (CYP7A1), the rate-limiting enzyme.
- CYP7A1 cholesterol 7a-hydroxylase
- FXR-deficient mice increased levels of blood cholesterol, bile acids, triglycerides, etc. became apparent (Sinai et al., Cell 102, pp731-744, 2000). Since bile acids promote intestinal cholesterol absorption, in FXR-deficient mice, the conversion of cholesterol to bile acids is promoted, but the increase in bile acid biosynthesis promotes intestinal cholesterol absorption. it is conceivable that.
- FXR activators are expected to have serum triglyceride and cholesterol lowering effects, and are promising candidates for preventive and therapeutic drugs for hyperlipidemia.
- An FXR activator is also useful as a therapeutic agent for intrahepatic cholestasis (Liu et al., J. Clin. Invest, pp. 1678-1687, 2003). Intrahepatic cholestasis is a disease in which the flow of bile in the liver is disrupted and hepatocytes are destroyed.
- FXR promotes the expression of the bile salt export pump gene (BSEP), which is a gene that is responsible for the excretion of bile acids into bile and is important for intestinal hepatic circulation. Is exempted from promoting elimination of cholesterol and improving intrahepatic cholestasis.
- BSEP bile salt export pump gene
- an HMG-CoA reductase inhibitor As a cholesterol lowering agent, an HMG-CoA reductase inhibitor has been highly evaluated clinically. However, it is effective enough to lower the target serum cholesterol level in patients with familial hypercholesterolemia who have high serum cholesterol levels or patients with coronary artery disease. Therefore, a more potent therapeutic agent for hyperlipidemia that is effective for such patients is desired.
- HMG-CoA reductase inhibitors the main mechanism of action of HMG-CoA reductase inhibitors is the indirect action of enhancing LDL receptor expression. However, the effect is limited, and it is also true that the concentration of serum cholesterol stops decreasing. Therefore, by developing drugs with a different mechanism of action from HMG-CoA reductase inhibitors,
- FXR activators have a different mechanism of action from HMG-CoA and may be useful cholesterol-lowering drugs. In addition, FXR activators have the potential to lower serum tridariceride, which holds promise as a preventive and therapeutic drug for hyperlipidemia.
- the present invention has been completed. It is based on the fact that the compounds represented by the formulas (1) and (2) exhibit FXR activating action.
- R represents the same or different and represents a functional group selected from hydrogen, an acyl group, an alkyl group and an aryl group. It also includes pharmaceutically acceptable salts such as sodium, potassium, magnesium, calcium and the like.
- FIG. 1 shows the results of a reporter gene assay showing the concentration-dependent FXR activity of each test compound.
- the compound represented by the chemical formula (1) or (2) and a salt thereof can be administered orally or parenterally when using it as a medicine. That is, it can be orally administered in the form of commonly used dosage forms, for example, tablets, capsules, syrups, suspensions, and the like, or in the form of solutions, emulsions, suspensions, and other liquid forms. It can be administered parenterally in the form of injections. It can also be administered rectally in the form of suppositories.
- the above-mentioned suitable dosage forms can be produced by incorporating the active compound into an acceptable usual carrier, excipient, binder, stabilizer and the like.
- an acceptable buffer, solubilizing agent, isotonic agent and the like can be added.
- the dose of the compound of the present invention is generally 120 mg / kg of body weight, preferably 5-10 mg / kg of body weight.
- the administration subject is a mammal, usually a human.
- FXR promotes transcription of downstream genes by binding to ligand and binding to FXR binding sequence (FXRE).
- FXRE FXR binding sequence
- a plasmid (reporter plasmid) in which 201 bp of the CMV promoter on the 3rd side and the enhanced yellow fluorescent protein (EYFP) gene are connected under the FXR binding sequence (FXRE), and the enhanced cyan fluorescent protein (E and FP) gene izs in the SV40 promoter Four types of plasmids, a plasmid containing the RXR gene and a plasmid containing the FXR gene, as plasmids for nuclear receptor expression, were introduced into COS7 cells.
- a test compound was added to the culture medium of the cells, and about 40 hours later, the medium was removed and the cells were washed with PBS, and then the fluorescence of EYFP and ECFP was measured.
- the fluorescence value of EYFP was corrected using the fluorescence value of ECFP measured as an internal standard. That is, the transcription activity of FXR was evaluated based on the value of (fluorescence value of EYFP) I (fluorescence value of ECFP).
- BSEP mRNA which is an index of FXR activity
- HuH-7 a cultured cell derived from liver cancer, was cultured in DMEM medium containing 10% FCS. The medium was replaced with phenol red-free DMEM containing 10% activated carbon-treated FCS, and after 6 hours, the medium was replaced with a test substance and phenol red-free DMEM containing 10% activated carbon-treated FCS, followed by culturing. Was done. After 24 hours, the cells were collected, and RNA was extracted using an RNeasy kit (QIAGEN). Using the obtained RNA, the mRNA of BSEP was quantified by TaqMan PCR. Each sample was corrected for RNA concentration using 18s rRNA.
- the above compounds are expected to reduce serum triglycerides and cholesterol by regulating the transcription activity of FXR.
- these compounds are compounds having structures different from bile acids, and are not metabolized to toxic lithocholic acid. Therefore, it can be expected as an effective drug for preventing and treating hyperlipidemia.
- the activation of FXR promotes the transcription of BSEP and is also effective as a preventive and therapeutic drug for intrahepatic cholestasis.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
Abstract
Description
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Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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JP2006511412A JPWO2005092328A1 (ja) | 2004-03-29 | 2005-03-03 | Fxr活性化化合物 |
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JP2004-094289 | 2004-03-29 | ||
JP2004094289 | 2004-03-29 |
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WO2005092328A1 true WO2005092328A1 (ja) | 2005-10-06 |
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PCT/JP2005/003600 WO2005092328A1 (ja) | 2004-03-29 | 2005-03-03 | Fxr活性化化合物 |
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WO (1) | WO2005092328A1 (ja) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1886685A1 (en) * | 2006-08-11 | 2008-02-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods, uses and compositions for modulating replication of hcv through the farnesoid x receptor (fxr) activation or inhibition |
WO2018178260A1 (en) | 2017-03-30 | 2018-10-04 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for reducing persistence and expression of episomal viruses |
EP3711762A1 (en) | 2013-09-11 | 2020-09-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A farnesoid x receptor agonsits foruse and pharmaceutical compositions for the treatment of chronic hepatitis b virus infection |
WO2021009332A1 (en) | 2019-07-18 | 2021-01-21 | Enyo Pharma | Method for decreasing adverse-effects of interferon |
WO2021144330A1 (en) | 2020-01-15 | 2021-07-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of fxr agonists for treating an infection by hepatitis d virus |
CN113549046A (zh) * | 2021-06-23 | 2021-10-26 | 山东大学 | 一种双联苄地钱素s衍生物及其制备方法和应用 |
WO2022152770A1 (en) | 2021-01-14 | 2022-07-21 | Enyo Pharma | Synergistic effect of a fxr agonist and ifn for the treatment of hbv infection |
WO2022229302A1 (en) | 2021-04-28 | 2022-11-03 | Enyo Pharma | Strong potentiation of tlr3 agonists effects using fxr agonists as a combined treatment |
Citations (4)
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JPS6092284A (ja) * | 1983-10-25 | 1985-05-23 | Otsuka Pharmaceut Co Ltd | ビスビベンジルジエ−テル誘導体 |
WO2002011708A2 (en) * | 2000-08-04 | 2002-02-14 | Symphar S.A. | Methods for inducing apolipoprotein e secretion |
WO2002072598A1 (en) * | 2001-03-12 | 2002-09-19 | Roberto Pellicciari | Steroids as agonists for fxr |
WO2003030612A2 (en) * | 2001-10-05 | 2003-04-17 | City Of Hope | Methods for modulating activity of the fxr nuclear receptor |
-
2005
- 2005-03-03 WO PCT/JP2005/003600 patent/WO2005092328A1/ja active Application Filing
- 2005-03-03 JP JP2006511412A patent/JPWO2005092328A1/ja active Pending
Patent Citations (4)
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JPS6092284A (ja) * | 1983-10-25 | 1985-05-23 | Otsuka Pharmaceut Co Ltd | ビスビベンジルジエ−テル誘導体 |
WO2002011708A2 (en) * | 2000-08-04 | 2002-02-14 | Symphar S.A. | Methods for inducing apolipoprotein e secretion |
WO2002072598A1 (en) * | 2001-03-12 | 2002-09-19 | Roberto Pellicciari | Steroids as agonists for fxr |
WO2003030612A2 (en) * | 2001-10-05 | 2003-04-17 | City Of Hope | Methods for modulating activity of the fxr nuclear receptor |
Non-Patent Citations (5)
Title |
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KESERU G.M. ET AL: "Molecular similarity analysis on biologically active macrocyclic bis (biphenyls)", JOURNAL OF MOLECULAR RECOGNITION, vol. 9, no. 2, 1996, pages 133 - 138, XP002989424 * |
SCHWARTNER C. ET AL: "Effect of marchantins and related compounds on 5-lipoxygenase and cyclooxygenase and their antioxidant properties: a structure activity relationship study", PHYTOMEDICINE, vol. 2, no. 2, 1995, pages 113 - 117, XP002989421 * |
SCHWARTNER C. ET AL: "Marchantins and related polyphenols from liverwort: physico-chemical studies of their radical-scavenging properties", FREE RADICAL BIOLOGY & MEDICINE, vol. 20, no. 2, 1996, pages 237 - 244, XP002989422 * |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1886685A1 (en) * | 2006-08-11 | 2008-02-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods, uses and compositions for modulating replication of hcv through the farnesoid x receptor (fxr) activation or inhibition |
WO2008017692A3 (en) * | 2006-08-11 | 2009-04-30 | Inst Nat Sante Rech Med | Methods, uses and compositions for modulating replication of hcv through the farnesoid x receptor (fxr) activation or inhibition |
EP2399575A2 (en) | 2006-08-11 | 2011-12-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods, uses and compositions for treatment of an infection by a virus of the family of flaviviridae through the farnesoid X receptor (FXR) inhibition |
EP2399988A2 (en) | 2006-08-11 | 2011-12-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Cell culture system for replication of HCV through the farnesoid X receptor (FXR) activation or inhibition and diagnostic method for HCV infection |
EP3711762A1 (en) | 2013-09-11 | 2020-09-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A farnesoid x receptor agonsits foruse and pharmaceutical compositions for the treatment of chronic hepatitis b virus infection |
WO2018178260A1 (en) | 2017-03-30 | 2018-10-04 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for reducing persistence and expression of episomal viruses |
WO2021009332A1 (en) | 2019-07-18 | 2021-01-21 | Enyo Pharma | Method for decreasing adverse-effects of interferon |
WO2021144330A1 (en) | 2020-01-15 | 2021-07-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of fxr agonists for treating an infection by hepatitis d virus |
WO2022152770A1 (en) | 2021-01-14 | 2022-07-21 | Enyo Pharma | Synergistic effect of a fxr agonist and ifn for the treatment of hbv infection |
WO2022229302A1 (en) | 2021-04-28 | 2022-11-03 | Enyo Pharma | Strong potentiation of tlr3 agonists effects using fxr agonists as a combined treatment |
CN113549046A (zh) * | 2021-06-23 | 2021-10-26 | 山东大学 | 一种双联苄地钱素s衍生物及其制备方法和应用 |
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