+

WO2013037482A1 - Agonistes du récepteur du farnésoïde x pour le traitement et la prévention du cancer - Google Patents

Agonistes du récepteur du farnésoïde x pour le traitement et la prévention du cancer Download PDF

Info

Publication number
WO2013037482A1
WO2013037482A1 PCT/EP2012/003814 EP2012003814W WO2013037482A1 WO 2013037482 A1 WO2013037482 A1 WO 2013037482A1 EP 2012003814 W EP2012003814 W EP 2012003814W WO 2013037482 A1 WO2013037482 A1 WO 2013037482A1
Authority
WO
WIPO (PCT)
Prior art keywords
fxr
cyclopropyl
fxr agonist
agonist
expression
Prior art date
Application number
PCT/EP2012/003814
Other languages
English (en)
Inventor
Ulrich Deuschle
Claus Kremoser
Original Assignee
Phenex Pharmaceuticals Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Phenex Pharmaceuticals Ag filed Critical Phenex Pharmaceuticals Ag
Publication of WO2013037482A1 publication Critical patent/WO2013037482A1/fr

Links

Classifications

    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the Farnesoid X Receptor (FXR, NR1H4) is a member of the nuclear hormone receptor superfamily, predominantly expressed in tissues exposed to high levels of bile acids, such as the entire gastrointestinal tract, the liver and the gallbladder. FXR mRNA can also be detected in tissues such as the adrenals, kidneys and adipose tissues (B. Goodwin et al., Mol. Cell 2000, 6, 517). FXR senses bile acids as endogenous ligands (D. J. Parks et al., Science 1999, 284, 1365), is a master regulator of bile acid homeostasis and prevents bile acid-induced liver toxicity by regulating directly and indirectly (e.g.
  • FXR farnesoid X receptor
  • Activation of FXR results in hepatoprotection in mouse models of non alcoholic fatty liver disease possibly mediated via a reduction of lipid accumulation, fibrosis and inflammation (S. Fiorucci et al., J. Pharmacol. Exp. Ther. 2005, 314, 584; S. Zhang et al., J. Hepatol. 2009, 51 , 380).
  • FXR controls the expression of FGF15 in the mouse and FGF19 in humans.
  • FGF19 injected into mice results in insulin sensitization, body weight and lipid lowering.
  • N-myc downregulated gene 2 (human gene NDRG2, mouse gene Ndrg2) was reported as a candidate tumor suppressor in human liver cancer metastasis (D. C. Lee et al., Cancer Res. 2008, 68, 4210). Furthermore, reduced NDRG2 expression was published for high-risk adenomas and colorectal carcinoma (A. Lorentzen et al., BMC Cancer 2007, 7, 192; Y. J. Kim et al., Carcinogenesis 2009, 30, 598; A. Piepoli et al., BMC Med. Genomics 2009, 2, 1 1 ; D. Chu et al., Mol. Cancer Ther. 201 1 , 10, 47), glioblastoma (M.
  • the RECK gene has been implicated in the suppression of malignancies through inhibition of matrix metalloproteases (MMPs). No anti-tumor effect in vivo was shown in the two above listed patent applications.
  • MMPs matrix metalloproteases
  • the expression of RECK is only found to be reduced in stage 1 but not in other stages of HCC, suggesting that RECK may play a role in early (stage 1) hepatocarcinogenesis but not in later stages (see Fig. 9 of EXAMPLE 9).
  • NDRG2 expression was found reduced in all HCC stages compatible with an important role of NDRG2 in hepatocarcinognesis of all stages.
  • the problem underlying the present invention is the provision of FXR agonists for use in the treatment or prevention of cancers, metastases, precancerogenic lesions or angiogenesis in the context of cancer in a patient. Said problem has been solved by FXR agonists which induce the expression of NDRG2 in a patient.
  • the invention is further based on the unexpected finding that agonists of FXR can reduce the growth rate and metastasis of SK- Hep-1 cells (human hepatocellular carcinoma cells) orthotopically transplanted into the livers of immunodeficient nude mice. Further the invention is based on the unexpected finding that agonists of FXR can even more efficiently reduce the growth rate and metastasis of SK-GI-18 cells (SK-Hep-1 derivative that contains a stably integrated FXR cDNA under control of the human CMV IE promoter and stably expresses human FXR (isoform 3 accession Nr. NM_005123)) when orthotopically transplanted into the livers of immunodeficient nude mice (see EXAMPLE 10).
  • At least one FXR agonist for use in increasing NDRG2 gene expression in a cell is provided, wherein the at least one FXR agonist is administered to a cell in an effective amount.
  • FXR agonist induces expression of the NDRG2 gene in the cell.
  • FXR is known to bind to IR-1 type Sequences within genes regulated by FXR.
  • IR-1 type elements are identified in the first introns of the NDRG2 genes of humans, mouse and rat (FIG. 2).
  • FIG. 2 When cloned into pGL4 (Promega), the human IR1 sequence was found to be functional in luciferase reporter gene assays in vitro (FIG. 2).
  • a mutated version of the NDRG2 IR-1 type element (FIG. 1) has lost functionality in this assay (FIG. 2).
  • NDRG2 mRNA was upregulated by the non-steroidal FXR agonist Px20350 in a dose dependent fashion in HepG2 cells (FIG. 5A). This upregulation was pronounced when stably expressing human FXR in the stable HepG2 derivative HepG2-FXR5 (FIG. 5A). In HepG2-FXR5 cells, NDRG2 mRNA was also upregulated by the synthetic steroidal FXR agonist 6-ECDCA and with a lower potency by the natural bile acid CDCA (FIG. 5B potencies are: Px20350 EC50 66 nM, 6-EDCA 280 nM CDCA 33 ⁇ ). An upregulation of SHP mRNA was detected with non-steroidal and steroidal FXR agonists in both cell lines as well.
  • SK-Hep-1 cells are hepatoma cells, that do express rather low levels of FXR.
  • a stable SK- Hep-1 derivative (named SK-GI-18) was generated by stably transfecting a human FXR cDNA under control of a CMV promoter. While the levels of NDRG2 and the induction of NDRG2 by Px20350 was rather low in SK-Hep-1 cells, in SK-GI-18 cells, the relative levels of NDRG2 mRNA was increased (when normalized to TATA box binding protein mRNA) and the induciblity of NDRG2 mRNA by Px20350was increased (FIG. 6).
  • SK-Hep-1 cells do not change growth rate in vitro in response to the FXR agonist Px20350, SK-GI-18 cells that overexpress FXR do decrease their in vitro growth rate in a dose dependent fashion (FIG. 7).
  • RECK is described as a FXR modulated gene linked to a possible anti-malignant activity of FXR modulators.
  • the finding that RECK expression is not reduced in the more severe hepatocellular carcinoma stages II, IIIA and IV suggests that RECK could play only a significant role in very early stages of hepatocellular carcinoma. This is in contrast to NDRG2 and SHP, which are reduced in all HCC stages in a stage-dependent fashion (FIG. 9).
  • Exemplary tumors include but are not limited to hepatocellular carcinoma, colorectal cancer, gastric cancer, renal cancer, prostate cancer, adrenal cancer, pancreatic cancer, breast cancer, bladder cancer, salivary gland cancer, ovarian cancer, uterine body cancer, and lung cancer.
  • the term "agonist" refers to an agent that triggers a response that is at least one response triggered by binding of an endogenous ligand of the receptor to the receptor.
  • the agonist may act directly or indirectly on a second agent that itself modulates the activity of the receptor.
  • the agonist may act indirectly by modulating the activity of one or more agent(s) that modulate the amount of FXR mRNA or FXR protein in certain cells of a patient.
  • the at least one response of the receptor is an activity of the receptor that can be measured with assays including but not limited to physiological, pharmacological, and biochemical assays.
  • agent refers to a substance including, but not limited to a chemical compound, such as a small molecule or a complex organic compound, a protein, such as an antibody or antibody fragment or a protein comprising an antibody fragment, or a genetic construct which acts at the DNA or mRNA level in an organism.
  • metalstatic refers to the process by which a cell, a group of cells, or a malignancy spreads from a site to sites not adjacent to the first site.
  • the FXR agonist is selected from a compound according to Formula (1 ), an enantiomer, diastereomer, tautomer, solvate, prodrug or pharmaceutical acceptable salt thereof
  • a therapeutically effective dosage should produce a serum concentration of active agent of from about 0.1 ng/mL to about 50-100 g/mL
  • the pharmaceutical compositions typically should provide a dosage of from about 0.001 mg to about 2000 mg of FXR agonist per kilogram of body weight per day.
  • Pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 1000 mg, such as from about 10 to about 500 mg of the active agent or a combination of agents per dosage unit form.
  • compositions are intended to be administered by a suitable route, including by way of example and without limitation orally, parenterally, rectally, topically and locally.
  • a suitable route including by way of example and without limitation orally, parenterally, rectally, topically and locally.
  • capsules and tablets can be used for oral administration.
  • the compositions are in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components, in any combination: a sterile diluent, including by way of example without limitation, water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent including by way of example without limitation, water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent
  • antimicrobial agents such as benzyl alcohol and methyl parab
  • the resulting mixture may be a solution, suspension, emulsion or the like.
  • the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the agent in the selected carrier or vehicle.
  • the effective concentration is sufficient for treating one or more symptoms of at least one malignancy and may be empirically determined.
  • the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, such as, by way of example and without limitation, acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.
  • auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, such as, by way of example and without limitation, acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.
  • auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, such as, by way of example and without limitation, acetate, sodium citrate, cyclodextr
  • Oral pharmaceutical dosage forms include, by way of example and without limitation, solid, gel and liquid.
  • Solid dosage forms include tablets, capsules, granules, and bulk powders.
  • Oral tablets include compressed, chewable lozenges and tablets which may be enteric-coated, sugar-coated or film-coated.
  • Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.
  • Disintegrating agents include, by way of example and without limitation, crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose.
  • Coloring agents include, by way of example and without limitation, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate.
  • Sweetening agents include, by way of example and without limitation, sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any number of spray dried flavors.
  • dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil.
  • dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents.
  • the agents can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like.
  • a syrup may contain, in addition to the active agents, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics.
  • Solvents include by way of example and without limitation, glycerin, sorbitol, ethyl alcohol and syrup.
  • preservatives include without limitation glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
  • Non-aqueous liquids utilized in emulsions include by way of example and without limitation, mineral oil and cottonseed oil.
  • Emulsifying agents include by way of example and without limitation, gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate.
  • Sources of carbon dioxide include, by way of example and without limitation, sodium bicarbonate and sodium carbonate.
  • Coloring agents include, by way of example and without limitation, any of the approved certified water soluble FD and C dyes, and mixtures thereof.
  • Flavoring agents include, by way of example and without limitation, natural flavors extracted from plants such fruits, and synthetic blends of agents which produce a pleasant taste sensation.
  • the solution or suspension in for example propylene carbonate, vegetable oils or triglycerides, is encapsulated in a gelatin capsule.
  • a gelatin capsule Such solutions, and the preparation and encapsulation thereof, are disclosed in US 4328245, 4409239, and 4410545.
  • the solution e.g., for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be easily measured for administration.
  • a pharmaceutically acceptable liquid carrier e.g., water
  • Tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
  • they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate.
  • Parenteral administration generally characterized by injection, either subcutaneously, intramuscularly or intravenously is also contemplated herein.
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • Suitable excipients include by way of example and without limitation, water, saline, dextrose, glycerol or ethanol.
  • compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
  • Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
  • the unit-dose parenteral preparations are packaged in an ampoule, a vial or a syringe with a needle. Preparations for parenteral administration should be sterile, as is known and practiced in the art.
  • Assays that do not require washing or liquid separation steps can be used for high throughput screening systems and include biochemical assays such as fluorescence polarization assays (see e.g. J. C. Owicki, J. Biomol. Screen. 2000, 5, 297) scintillation proximity assays (SPA) (see e.g. J. W. Carpenter et al., Methods Mol. Biol. 2002, 190, 31) and fluorescence resonance energy transfer energy transfer (FRET) or time resolved FRET based coactivator recruitment assays (R. Mukherjee et al., J. Steroid Biochem. Mol. Biol. 2002, 81 , 217; G. Zhou et al., Mol. Endocrinol. 1998, 12, 1594).
  • biochemical assays such as fluorescence polarization assays (see e.g. J. C. Owicki, J. Biomol. Screen. 2000, 5, 297) scintillation proximity assays (SPA)
  • Reporter plasmids may be constructed using standard molecular biological techniques by placing cDNA encoding for the reporter gene downstream from a suitable minimal promoter.
  • luciferase reporter plasmids may be constructed by placing cDNA encoding firefly luciferase immediately down stream from the herpes virus thymidine kinase promoter (located at nucleotides residues -105 to +51 of the thymidine kinase nucleotide sequence) which is linked in turn to the various response elements.
  • a third cell based assay of utility for screening agents is a mammalian two-hybrid assay that measures the ability of the nuclear hormone receptor to interact with a cofactor in the presence of a ligand (see e.g. US 5667973, US 5283173 and US 5468614).
  • the basic approach is to create three plasmid constructs that enable the interaction of FXR with the interacting protein to be coupled to a transcriptional readout within a living cell.
  • the first construct is an expression plasmid for expressing a fusion protein comprising the interacting protein, or a portion of that protein containing the interacting domain, fused to a GAL4 DNA binding domain.
  • NDRG2 inhibits the secretion and activities of multiple MMPs.
  • the MMP may be MMP-9.
  • the amount of MMPs secreted from a cell treated in the absence or presence of a agent can be measured using standard assays including but not limited to Western blot, enzyme linked immunosorbent assay, and gelatin zymography. Agonists of FXR may induce the expression of NDRG2, thereby leading to decreased secretion of MMPs.
  • Cells that express FXR endogenously include, by way of example and without limitation: hepatocytes, including primary hepatocytes isolated from human, monkey, mouse, or rat, or hepatocyte cell lines, including HepG2, Huh7, or SK-Hep-1 cells; and intestinal cells including HT-29, CaCo2 and FHs 74 Int.
  • hepatocytes including primary hepatocytes isolated from human, monkey, mouse, or rat, or hepatocyte cell lines, including HepG2, Huh7, or SK-Hep-1 cells
  • intestinal cells including HT-29, CaCo2 and FHs 74 Int.
  • stage I cancers are often localized and are usually curable.
  • Stage II and IIIA cancers are usually more advanced and may have invaded the surrounding tissues and spread to lymph nodes.
  • Stage IV cancers include metastatic cancers that have spread to sites outside of lymph nodes.
  • NDRG2 expression has been shown to correlate with beneficial prognoses for several malignancies including hepatocellular carcinoma, colorectal cancer, and breast cancer.
  • Restoration of NDRG2 expression in malignant cells can suppress their invasive, metastatic, and angiogenic activities through inhibition of matrix metalloproteases.
  • NDRG2 expression in tumor cells has been shown to suppress MMP-2 and CD24 expression.
  • Methods of inducing NDRG2 expression are provided herein through administering at least one FXR agonist.
  • the FXR agonist, or pharmaceutically acceptable derivative thereof, is administered simultaneously with, prior to, or after administration of one or more of the above agents.
  • FIG. 8 shows the migration of SK-GI-18 and SK-Hep-1 cells in presence of DMSO or 1 ⁇ Px20350 in the growth medium.
  • FXR NR1 H4
  • NDRG2 NDRG2
  • SHP NR0B2
  • RECK mRNA levels were quantified in 8 normal, 34 HCC and 12 non-HCC liver disease (LD) cDNA ' s purchased from ORIGENE (Cat. Nr. LVRT501 ) by q-RT-PCR.
  • the cDNA samples have been obtained from patient liver samples verified by pathologists prior to isolation of RNA and conversion to cDNA which were normalized against beta-actin by RT-PCR and arrayed onto 96 well plate.
  • FIG. 9 Decreased expression of FXR and FXR target genes in human HCC.
  • a total of 34 HCC cDNA samples from different stages (7 samples stage I, 8 samples of stages II and 111 A, 12 non-HCC liver disease (LD) and 8 normal liver samples were studied.
  • the mRNA expression for the indicated genes (FXR (NR1 H4), NDRG2, SHP (NR0B2) and RECK) was determined by Real Time PCR on an ABI HT 7900 Real Time PCR device and the data are expressed as mean+SEM.
  • SK-Hep-1 cells and SK-GI-18 cells were grown in RPMI medium (Sigma) supplemented with 8.6% FCS (Sigma) and 20 mM Alanyl-Glutamine (Sigma).
  • NMRI female nude mice (Charles River, Sulzfeld, Germany) were implanted with 5x106 cell (either SK-Hep-1 or SK-GI-18) by injection into one liver lobe at experimental day 0 (Experiments done at Oncotest GmbH, Freiburg, Germany according to Oncotest SOP).
  • Sorafenib does reduce primary tumor formation and metastasis of tumor cells in mice receiving SK-Hep-1 or SK-GI-18 cells comparably well.
  • the FXR agonists Px20606 and also Px21256 do reduce the tumor growth and metastasis more effectively in SK-GI-18 cells that do stably express human FXR isoform 3 compared to SK-Hep-1 cells that do express only very low to undetectable levels of endogenous FXR.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un agoniste du récepteur du farnésoïde X (FXR) destiné à être utilisé dans le traitement ou la prévention de certains cancers, de certaines métastases, de certaines lésions pré-cancéreuses ou de l'angiogenèse dans le contexte d'un cancer chez un patient, l'agoniste du récepteur du farnésoïde X (FXR) étant administré en une quantité thérapeutiquement efficace au patient. La présente invention concerne en outre un agoniste du FXR destiné à être utilisé pour induire l'expression du gène NDRG2 dans certains tissus d'un patient, l'agoniste de FXR étant administré en une quantité thérapeutiquement efficace au patient. La présente invention concerne en outre un agoniste de FXR destiné à être utilisé pour réduire le taux de prolifération, la migration, la métastase ou l'angiogenèse de certaines tumeurs.
PCT/EP2012/003814 2011-09-15 2012-09-11 Agonistes du récepteur du farnésoïde x pour le traitement et la prévention du cancer WO2013037482A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201161535061P 2011-09-15 2011-09-15
EP11007533.0 2011-09-15
US61/535,061 2011-09-15
EP11007533 2011-09-15

Publications (1)

Publication Number Publication Date
WO2013037482A1 true WO2013037482A1 (fr) 2013-03-21

Family

ID=47882642

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2012/003814 WO2013037482A1 (fr) 2011-09-15 2012-09-11 Agonistes du récepteur du farnésoïde x pour le traitement et la prévention du cancer

Country Status (1)

Country Link
WO (1) WO2013037482A1 (fr)

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106995416A (zh) * 2016-01-26 2017-08-01 上海翰森生物医药科技有限公司 Fxr激动剂及其制备方法和应用
WO2017128896A1 (fr) * 2016-01-26 2017-08-03 江苏豪森药业集团有限公司 Agoniste de fxr et son procédé de préparation et utilisation associée
WO2017147047A1 (fr) * 2016-02-22 2017-08-31 Alios Biopharma, Inc. Modulateurs de fxr et leurs procédés d'utilisation
WO2017180577A1 (fr) * 2016-04-13 2017-10-19 Intercept Pharmaceuticals, Inc. Procédés de traitement du cancer
EP3257847A1 (fr) * 2016-06-13 2017-12-20 Gilead Sciences, Inc. Modulateurs du fxr (nr1h4)
US20180030083A1 (en) * 2015-02-16 2018-02-01 Suzhou Zelgen Biopharmaceuticals Co., Ltd. Deuterated chenodeoxycholic acid derivative and pharmaceutical composition comprising compound thereof
US20180148470A1 (en) * 2015-04-28 2018-05-31 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Cholic acid derivative, and preparation method and medical use thereof
US20180256600A1 (en) * 2017-03-07 2018-09-13 Intercept Pharmaceuticals, Inc. Methods of treating cancer
US10080742B2 (en) 2016-04-26 2018-09-25 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
US10080743B2 (en) 2016-04-26 2018-09-25 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
US10080741B2 (en) 2016-04-26 2018-09-25 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
WO2018178260A1 (fr) 2017-03-30 2018-10-04 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour réduire la persistance et l'expression des virus épisomiques
US10138228B2 (en) 2016-05-18 2018-11-27 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use therof
US10144729B2 (en) 2016-05-18 2018-12-04 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
US10149835B2 (en) 2016-05-18 2018-12-11 Elmore Patent Law Group, P.C. Isoxazole derivatives as FXR agonists and methods of use thereof
CN109311849A (zh) * 2016-06-13 2019-02-05 吉利德科学公司 调节fxr(nr1h4)的化合物
US10220027B2 (en) 2011-07-13 2019-03-05 Gilead Sciences, Inc. FXR (NR1H4) binding and activity modulating compounds
US10450306B2 (en) 2016-10-04 2019-10-22 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
CN110430882A (zh) * 2017-03-07 2019-11-08 英特塞普特医药品公司 治疗癌症的方法
JP2019535811A (ja) * 2016-10-22 2019-12-12 へパジーン セラピューティクス インコーポレイテッド 複素環式ｆｘｒモジュレーター
US10597391B2 (en) 2016-10-26 2020-03-24 Enanta Pharmaceuticals, Inc. Urea-containing isoxazole derivatives as FXR agonists and methods of use thereof
US10689391B2 (en) 2017-12-12 2020-06-23 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
CN111413447A (zh) * 2020-04-09 2020-07-14 郑州大学第一附属医院 鹅去氧胆酸或/和牛磺酸鹅去氧胆酸在胆管癌诊断方面的应用
EP3711762A1 (fr) 2013-09-11 2020-09-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pharmaceutiques pour le traitement de l'infection par le virus de l'hépatite b chronique
WO2020198576A1 (fr) * 2019-03-28 2020-10-01 The Board Of Trustees Of The University Of Illinois Procédés de modulation de lymphocytes t régulateurs
USRE48286E1 (en) 2001-03-12 2020-10-27 Intercept Pharmaceuticals, Inc. Steroids as agonists for FXR
US10829486B2 (en) 2018-02-14 2020-11-10 Enanta Pharmacueticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
WO2021009332A1 (fr) 2019-07-18 2021-01-21 Enyo Pharma Procédé pour diminuer les effets secondaires de l'interféron
CN112341514A (zh) * 2019-08-06 2021-02-09 杜心赟 脱氧胆酸类化合物、药物组合物及其用途
EP3658150A4 (fr) * 2017-07-24 2021-03-31 Intercept Pharmaceuticals, Inc. Dérivés d'acide biliaire à marquage isotopique
US10988449B2 (en) 2017-04-12 2021-04-27 Il Dong Pharmaceutical Co., Ltd. Isoxazole derivatives as nuclear receptor agonists and uses thereof
WO2021144330A1 (fr) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'agonistes de fxr pour traiter une infection par le virus de l'hépatite d
US11225473B2 (en) 2019-01-15 2022-01-18 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
CN114656460A (zh) * 2020-12-22 2022-06-24 江苏天士力帝益药业有限公司 一种新型吡嗪结构fxr激动剂、制备方法及应用
WO2022152770A1 (fr) 2021-01-14 2022-07-21 Enyo Pharma Effet synergique d'un agoniste de fxr et d'ifn pour le traitement d'une infection par le virus de l'hépatite b
WO2022229302A1 (fr) 2021-04-28 2022-11-03 Enyo Pharma Potentialisation forte d'effets d'agonistes de tlr3 à l'aide d'agonistes de fxr en tant que traitement combiné
US11524005B2 (en) 2019-02-19 2022-12-13 Gilead Sciences, Inc. Solid forms of FXR agonists
US11555032B2 (en) 2019-05-13 2023-01-17 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
CN115666528A (zh) * 2020-03-18 2023-01-31 梅塔科林公司 法尼醇x受体激动剂的制剂
US11833150B2 (en) 2017-03-28 2023-12-05 Gilead Sciences, Inc. Methods of treating liver disease
US11958879B2 (en) 2015-03-31 2024-04-16 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
CN118846078A (zh) * 2024-07-02 2024-10-29 中国人民解放军空军军医大学 Ndrg2基因联合分子靶向抑制剂在制备肾细胞癌治疗药物中的应用

Citations (75)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3710795A (en) 1970-09-29 1973-01-16 Alza Corp Drug-delivery device with stretched, rate-controlling membrane
USRE28819E (en) 1972-12-08 1976-05-18 Syntex (U.S.A.) Inc. Dialkylated glycol compositions and medicament preparations containing same
US4044126A (en) 1972-04-20 1977-08-23 Allen & Hanburys Limited Steroidal aerosol compositions and process for the preparation thereof
US4328245A (en) 1981-02-13 1982-05-04 Syntex (U.S.A.) Inc. Carbonate diester solutions of PGE-type compounds
US4358603A (en) 1981-04-16 1982-11-09 Syntex (U.S.A.) Inc. Acetal stabilized prostaglandin compositions
US4364923A (en) 1972-04-20 1982-12-21 Allen & Hanburs Limited Chemical compounds
US4409239A (en) 1982-01-21 1983-10-11 Syntex (U.S.A.) Inc. Propylene glycol diester solutions of PGE-type compounds
US4410545A (en) 1981-02-13 1983-10-18 Syntex (U.S.A.) Inc. Carbonate diester solutions of PGE-type compounds
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
US5033252A (en) 1987-12-23 1991-07-23 Entravision, Inc. Method of packaging and sterilizing a pharmaceutical product
US5052558A (en) 1987-12-23 1991-10-01 Entravision, Inc. Packaged pharmaceutical product
US5070012A (en) 1988-03-30 1991-12-03 The Board Of Trustees Of The Leland Stanford Junior University Monitoring of cells and trans-activating transcription elements
US5221623A (en) 1986-07-22 1993-06-22 Boyce Thompson Institute For Plant Research, Inc. Use of bacterial luciferase structural genes for cloning and monitoring gene expression in microorganisms and for tagging and identification of genetically engineered organisms
US5283173A (en) 1990-01-24 1994-02-01 The Research Foundation Of State University Of New York System to detect protein-protein interactions
US5323907A (en) 1992-06-23 1994-06-28 Multi-Comp, Inc. Child resistant package assembly for dispensing pharmaceutical medications
WO1995018380A1 (fr) 1993-12-30 1995-07-06 The Salk Institute For Biological Studies Nouvelles utilisations de produits de recombinaison de recepteurs de gal4
US5650289A (en) 1990-09-10 1997-07-22 Promega Corporation Luciferase assay compositions
US5674713A (en) 1985-12-02 1997-10-07 The Regents Of The University Of California DNA sequences encoding coleoptera luciferase activity
US5683888A (en) 1989-07-22 1997-11-04 University Of Wales College Of Medicine Modified bioluminescent proteins and their use
US5709874A (en) 1993-04-14 1998-01-20 Emory University Device for local drug delivery and methods for using the same
US5741657A (en) 1995-03-20 1998-04-21 The Regents Of The University Of California Fluorogenic substrates for β-lactamase and methods of use
US5759542A (en) 1994-08-05 1998-06-02 New England Deaconess Hospital Corporation Compositions and methods for the delivery of drugs by platelets for the treatment of cardiovascular and other diseases
US5840674A (en) 1990-11-01 1998-11-24 Oregon Health Sciences University Covalent microparticle-drug conjugates for biological targeting
US5843746A (en) 1994-07-27 1998-12-01 Kikkoman Corporation Biotinated firefly luciferase, a gene for biotinated firefly luciferase, a recombinant DNA, a process for producing biotinated luciferase and a bioluminescent analysis method
US5860957A (en) 1997-02-07 1999-01-19 Sarcos, Inc. Multipathway electronically-controlled drug delivery system
US5900252A (en) 1990-04-17 1999-05-04 Eurand International S.P.A. Method for targeted and controlled release of drugs in the intestinal tract and more particularly in the colon
US5948433A (en) 1997-08-21 1999-09-07 Bertek, Inc. Transdermal patch
US5955604A (en) 1996-10-15 1999-09-21 The Regents Of The University Of California Substrates for β-lactamase and uses thereof
US5972366A (en) 1994-11-28 1999-10-26 The Unites States Of America As Represented By The Secretary Of The Army Drug releasing surgical implant or dressing material
US5983134A (en) 1995-04-23 1999-11-09 Electromagnetic Bracing Systems Inc. Electrophoretic cuff apparatus drug delivery system
US5985307A (en) 1993-04-14 1999-11-16 Emory University Device and method for non-occlusive localized drug delivery
US5985317A (en) 1996-09-06 1999-11-16 Theratech, Inc. Pressure sensitive adhesive matrix patches for transdermal delivery of salts of pharmaceutical agents
US6004534A (en) 1993-07-23 1999-12-21 Massachusetts Institute Of Technology Targeted polymerized liposomes for improved drug delivery
US6010715A (en) 1992-04-01 2000-01-04 Bertek, Inc. Transdermal patch incorporating a polymer film incorporated with an active agent
US6024975A (en) 1992-04-08 2000-02-15 Americare International Diagnostics, Inc. Method of transdermally administering high molecular weight drugs with a polymer skin enhancer
US6039975A (en) 1995-10-17 2000-03-21 Hoffman-La Roche Inc. Colon targeted delivery system
US6048736A (en) 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
US6060082A (en) 1997-04-18 2000-05-09 Massachusetts Institute Of Technology Polymerized liposomes targeted to M cells and useful for oral or mucosal drug delivery
US6071495A (en) 1989-12-22 2000-06-06 Imarx Pharmaceutical Corp. Targeted gas and gaseous precursor-filled liposomes
WO2000037077A1 (fr) 1998-12-23 2000-06-29 Glaxo Group Limited Methodes de titrage de ligands de recepteurs nucleaires
US6120751A (en) 1997-03-21 2000-09-19 Imarx Pharmaceutical Corp. Charged lipids and uses for the same
US6131570A (en) 1998-06-30 2000-10-17 Aradigm Corporation Temperature controlling device for aerosol drug delivery
US6139865A (en) 1996-10-01 2000-10-31 Eurand America, Inc. Taste-masked microcapsule compositions and methods of manufacture
US6167301A (en) 1995-08-29 2000-12-26 Flower; Ronald J. Iontophoretic drug delivery device having high-efficiency DC-to-DC energy conversion circuit
US6253872B1 (en) 1996-05-29 2001-07-03 Gmundner Fertigteile Gesellschaft M.B.H & Co., Kg Track soundproofing arrangement
US6256533B1 (en) 1999-06-09 2001-07-03 The Procter & Gamble Company Apparatus and method for using an intracutaneous microneedle array
US6261595B1 (en) 2000-02-29 2001-07-17 Zars, Inc. Transdermal drug patch with attached pocket for controlled heating device
US6267983B1 (en) 1997-10-28 2001-07-31 Bando Chemical Industries, Ltd. Dermatological patch and process for producing thereof
US6271359B1 (en) 1999-04-14 2001-08-07 Musc Foundation For Research Development Tissue-specific and pathogen-specific toxic agents and ribozymes
US6274552B1 (en) 1993-03-18 2001-08-14 Cytimmune Sciences, Inc. Composition and method for delivery of biologically-active factors
US6316652B1 (en) 1995-06-06 2001-11-13 Kosta Steliou Drug mitochondrial targeting agents
WO2003015771A1 (fr) 2001-08-13 2003-02-27 Lion Bioscience Ag Composes de liaison au recepteur nucleaire fxr nr1h4
WO2004048349A1 (fr) 2002-11-22 2004-06-10 Smithkline Beecham Corporation Agonistes de recepteur farnesoide x
WO2007076260A2 (fr) 2005-12-19 2007-07-05 Smithkline Beecham Corporation Agonistes de recepteur de farnesoide x
WO2007092751A2 (fr) 2006-02-03 2007-08-16 Eli Lilly And Company Composés et procédés pour moduler fxr
WO2007110237A2 (fr) * 2006-03-28 2007-10-04 Novartis Ag Amides heterocycliques destines a une utilisation en tant que produits pharmaceutiques
WO2007140174A2 (fr) 2006-05-24 2007-12-06 Eli Lilly And Company Composés et méthodes de modulation de fxr
WO2007140183A1 (fr) 2006-05-24 2007-12-06 Eli Lilly And Company Agonistes de récepteur de farnesoide x
WO2008025540A1 (fr) 2006-08-29 2008-03-06 Phenex Pharmaceuticals Ag Composés hétérocycliques se liant au fxr
WO2008025539A1 (fr) 2006-08-29 2008-03-06 Phenex Pharmaceuticals Ag Composés de liaison au fxr hétérocycliques
WO2008051942A2 (fr) 2006-10-24 2008-05-02 Smithkline Beecham Corporation Agonistes du récepteur farnésoïde x
WO2008073825A1 (fr) 2006-12-08 2008-06-19 Exelixis, Inc. Modulateurs lxr et fxr
US20080299118A1 (en) 2007-06-01 2008-12-04 Wyeth FXR Agonists for the Treatment of Malignancies
WO2008157270A1 (fr) 2007-06-13 2008-12-24 Smithkline Beecham Corporation Agonistes de récepteur x de farnesoïde
WO2009005998A1 (fr) 2007-07-02 2009-01-08 Smithkline Beecham Corporation Agonistes du récepteur de farnésoïde x
WO2009012125A1 (fr) 2007-07-16 2009-01-22 Eli Lilly And Company Composés et procédés pour moduler le fxr
WO2009027264A1 (fr) 2007-08-27 2009-03-05 F. Hoffmann-La Roche Ag Dérivés de benzimidazole utilisés comme agonistes du récepteur fxr
US20090131409A1 (en) 2007-10-22 2009-05-21 Wyeth 1,4,5,6,7,8-HEXAHYDRO -PYRROLO[2,3-d]AZEPINES AND -IMIDAZO[4,5-d]AZEPINES AS MODULATORS OF NUCLEAR RECEPTOR ACTIVITY
WO2009080555A2 (fr) 2007-12-21 2009-07-02 F. Hoffmann-La Roche Ag Dérivés de benzimidazole substitués par carboxyle ou hydroxyle
WO2009127321A1 (fr) 2008-04-18 2009-10-22 Merck Patent Gmbh, Dérivés de benzofurane, benzothiophène, benzothiazol en tant que modulateurs de fxr
WO2009149795A2 (fr) 2008-05-26 2009-12-17 Phenex Pharmaceuticals Ag Composés de liaison à fxr substitués par cyclopropyle, hétérocycliques
WO2010028981A1 (fr) 2008-09-11 2010-03-18 F. Hoffmann-La Roche Ag Nouveaux dérivés de benzimidazole
WO2010034649A1 (fr) 2008-09-25 2010-04-01 F. Hoffmann-La Roche Ag Indazole 2,3-substitué ou 4,5,6,7-tétrahydro-indazoles en tant que modulateurs de fxr contre la dyslipidémie et les maladies associées
WO2010034657A1 (fr) 2008-09-25 2010-04-01 F. Hoffmann-La Roche Ag Dérivés de 3-amino-indazole ou de 3-amino-4,5,6,7-tétrahydro-indazole
WO2011020615A1 (fr) 2009-08-19 2011-02-24 Phenex Pharmaceuticals Ag Nouveaux composés se liant au fxr (nr1 h4) et modulant son activité

Patent Citations (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3710795A (en) 1970-09-29 1973-01-16 Alza Corp Drug-delivery device with stretched, rate-controlling membrane
US4044126A (en) 1972-04-20 1977-08-23 Allen & Hanburys Limited Steroidal aerosol compositions and process for the preparation thereof
US4364923A (en) 1972-04-20 1982-12-21 Allen & Hanburs Limited Chemical compounds
US4414209A (en) 1972-04-20 1983-11-08 Allen & Hanburys Limited Micronized aerosol steroids
USRE28819E (en) 1972-12-08 1976-05-18 Syntex (U.S.A.) Inc. Dialkylated glycol compositions and medicament preparations containing same
US4328245A (en) 1981-02-13 1982-05-04 Syntex (U.S.A.) Inc. Carbonate diester solutions of PGE-type compounds
US4410545A (en) 1981-02-13 1983-10-18 Syntex (U.S.A.) Inc. Carbonate diester solutions of PGE-type compounds
US4358603A (en) 1981-04-16 1982-11-09 Syntex (U.S.A.) Inc. Acetal stabilized prostaglandin compositions
US4409239A (en) 1982-01-21 1983-10-11 Syntex (U.S.A.) Inc. Propylene glycol diester solutions of PGE-type compounds
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
US5674713A (en) 1985-12-02 1997-10-07 The Regents Of The University Of California DNA sequences encoding coleoptera luciferase activity
US5221623A (en) 1986-07-22 1993-06-22 Boyce Thompson Institute For Plant Research, Inc. Use of bacterial luciferase structural genes for cloning and monitoring gene expression in microorganisms and for tagging and identification of genetically engineered organisms
US5033252A (en) 1987-12-23 1991-07-23 Entravision, Inc. Method of packaging and sterilizing a pharmaceutical product
US5052558A (en) 1987-12-23 1991-10-01 Entravision, Inc. Packaged pharmaceutical product
US5070012A (en) 1988-03-30 1991-12-03 The Board Of Trustees Of The Leland Stanford Junior University Monitoring of cells and trans-activating transcription elements
US5683888A (en) 1989-07-22 1997-11-04 University Of Wales College Of Medicine Modified bioluminescent proteins and their use
US6071495A (en) 1989-12-22 2000-06-06 Imarx Pharmaceutical Corp. Targeted gas and gaseous precursor-filled liposomes
US5283173A (en) 1990-01-24 1994-02-01 The Research Foundation Of State University Of New York System to detect protein-protein interactions
US5468614A (en) 1990-01-24 1995-11-21 The Research Foundation Of State University Of New York System to detect protein-protein interactions
US5667973A (en) 1990-01-24 1997-09-16 The Research Foundation Of State University Of New York System to detect protein-protein interactions
US5900252A (en) 1990-04-17 1999-05-04 Eurand International S.P.A. Method for targeted and controlled release of drugs in the intestinal tract and more particularly in the colon
US5650289A (en) 1990-09-10 1997-07-22 Promega Corporation Luciferase assay compositions
US5840674A (en) 1990-11-01 1998-11-24 Oregon Health Sciences University Covalent microparticle-drug conjugates for biological targeting
US6010715A (en) 1992-04-01 2000-01-04 Bertek, Inc. Transdermal patch incorporating a polymer film incorporated with an active agent
US6024975A (en) 1992-04-08 2000-02-15 Americare International Diagnostics, Inc. Method of transdermally administering high molecular weight drugs with a polymer skin enhancer
US5323907A (en) 1992-06-23 1994-06-28 Multi-Comp, Inc. Child resistant package assembly for dispensing pharmaceutical medications
US6274552B1 (en) 1993-03-18 2001-08-14 Cytimmune Sciences, Inc. Composition and method for delivery of biologically-active factors
US5985307A (en) 1993-04-14 1999-11-16 Emory University Device and method for non-occlusive localized drug delivery
US5709874A (en) 1993-04-14 1998-01-20 Emory University Device for local drug delivery and methods for using the same
US6004534A (en) 1993-07-23 1999-12-21 Massachusetts Institute Of Technology Targeted polymerized liposomes for improved drug delivery
WO1995018380A1 (fr) 1993-12-30 1995-07-06 The Salk Institute For Biological Studies Nouvelles utilisations de produits de recombinaison de recepteurs de gal4
US5843746A (en) 1994-07-27 1998-12-01 Kikkoman Corporation Biotinated firefly luciferase, a gene for biotinated firefly luciferase, a recombinant DNA, a process for producing biotinated luciferase and a bioluminescent analysis method
US5759542A (en) 1994-08-05 1998-06-02 New England Deaconess Hospital Corporation Compositions and methods for the delivery of drugs by platelets for the treatment of cardiovascular and other diseases
US5972366A (en) 1994-11-28 1999-10-26 The Unites States Of America As Represented By The Secretary Of The Army Drug releasing surgical implant or dressing material
US5741657A (en) 1995-03-20 1998-04-21 The Regents Of The University Of California Fluorogenic substrates for β-lactamase and methods of use
US5983134A (en) 1995-04-23 1999-11-09 Electromagnetic Bracing Systems Inc. Electrophoretic cuff apparatus drug delivery system
US6316652B1 (en) 1995-06-06 2001-11-13 Kosta Steliou Drug mitochondrial targeting agents
US6167301A (en) 1995-08-29 2000-12-26 Flower; Ronald J. Iontophoretic drug delivery device having high-efficiency DC-to-DC energy conversion circuit
US6039975A (en) 1995-10-17 2000-03-21 Hoffman-La Roche Inc. Colon targeted delivery system
US6253872B1 (en) 1996-05-29 2001-07-03 Gmundner Fertigteile Gesellschaft M.B.H & Co., Kg Track soundproofing arrangement
US5985317A (en) 1996-09-06 1999-11-16 Theratech, Inc. Pressure sensitive adhesive matrix patches for transdermal delivery of salts of pharmaceutical agents
US6139865A (en) 1996-10-01 2000-10-31 Eurand America, Inc. Taste-masked microcapsule compositions and methods of manufacture
US5955604A (en) 1996-10-15 1999-09-21 The Regents Of The University Of California Substrates for β-lactamase and uses thereof
US5860957A (en) 1997-02-07 1999-01-19 Sarcos, Inc. Multipathway electronically-controlled drug delivery system
US6120751A (en) 1997-03-21 2000-09-19 Imarx Pharmaceutical Corp. Charged lipids and uses for the same
US6060082A (en) 1997-04-18 2000-05-09 Massachusetts Institute Of Technology Polymerized liposomes targeted to M cells and useful for oral or mucosal drug delivery
US5948433A (en) 1997-08-21 1999-09-07 Bertek, Inc. Transdermal patch
US6267983B1 (en) 1997-10-28 2001-07-31 Bando Chemical Industries, Ltd. Dermatological patch and process for producing thereof
US6048736A (en) 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
US6131570A (en) 1998-06-30 2000-10-17 Aradigm Corporation Temperature controlling device for aerosol drug delivery
WO2000037077A1 (fr) 1998-12-23 2000-06-29 Glaxo Group Limited Methodes de titrage de ligands de recepteurs nucleaires
US6271359B1 (en) 1999-04-14 2001-08-07 Musc Foundation For Research Development Tissue-specific and pathogen-specific toxic agents and ribozymes
US6256533B1 (en) 1999-06-09 2001-07-03 The Procter & Gamble Company Apparatus and method for using an intracutaneous microneedle array
US6261595B1 (en) 2000-02-29 2001-07-17 Zars, Inc. Transdermal drug patch with attached pocket for controlled heating device
WO2003015771A1 (fr) 2001-08-13 2003-02-27 Lion Bioscience Ag Composes de liaison au recepteur nucleaire fxr nr1h4
WO2004048349A1 (fr) 2002-11-22 2004-06-10 Smithkline Beecham Corporation Agonistes de recepteur farnesoide x
WO2007076260A2 (fr) 2005-12-19 2007-07-05 Smithkline Beecham Corporation Agonistes de recepteur de farnesoide x
WO2007092751A2 (fr) 2006-02-03 2007-08-16 Eli Lilly And Company Composés et procédés pour moduler fxr
WO2007110237A2 (fr) * 2006-03-28 2007-10-04 Novartis Ag Amides heterocycliques destines a une utilisation en tant que produits pharmaceutiques
WO2007140174A2 (fr) 2006-05-24 2007-12-06 Eli Lilly And Company Composés et méthodes de modulation de fxr
WO2007140183A1 (fr) 2006-05-24 2007-12-06 Eli Lilly And Company Agonistes de récepteur de farnesoide x
WO2008025540A1 (fr) 2006-08-29 2008-03-06 Phenex Pharmaceuticals Ag Composés hétérocycliques se liant au fxr
WO2008025539A1 (fr) 2006-08-29 2008-03-06 Phenex Pharmaceuticals Ag Composés de liaison au fxr hétérocycliques
WO2008051942A2 (fr) 2006-10-24 2008-05-02 Smithkline Beecham Corporation Agonistes du récepteur farnésoïde x
WO2008073825A1 (fr) 2006-12-08 2008-06-19 Exelixis, Inc. Modulateurs lxr et fxr
US20080299118A1 (en) 2007-06-01 2008-12-04 Wyeth FXR Agonists for the Treatment of Malignancies
WO2008157270A1 (fr) 2007-06-13 2008-12-24 Smithkline Beecham Corporation Agonistes de récepteur x de farnesoïde
WO2009005998A1 (fr) 2007-07-02 2009-01-08 Smithkline Beecham Corporation Agonistes du récepteur de farnésoïde x
WO2009012125A1 (fr) 2007-07-16 2009-01-22 Eli Lilly And Company Composés et procédés pour moduler le fxr
WO2009027264A1 (fr) 2007-08-27 2009-03-05 F. Hoffmann-La Roche Ag Dérivés de benzimidazole utilisés comme agonistes du récepteur fxr
US20090131409A1 (en) 2007-10-22 2009-05-21 Wyeth 1,4,5,6,7,8-HEXAHYDRO -PYRROLO[2,3-d]AZEPINES AND -IMIDAZO[4,5-d]AZEPINES AS MODULATORS OF NUCLEAR RECEPTOR ACTIVITY
WO2009080555A2 (fr) 2007-12-21 2009-07-02 F. Hoffmann-La Roche Ag Dérivés de benzimidazole substitués par carboxyle ou hydroxyle
WO2009127321A1 (fr) 2008-04-18 2009-10-22 Merck Patent Gmbh, Dérivés de benzofurane, benzothiophène, benzothiazol en tant que modulateurs de fxr
WO2009149795A2 (fr) 2008-05-26 2009-12-17 Phenex Pharmaceuticals Ag Composés de liaison à fxr substitués par cyclopropyle, hétérocycliques
WO2010028981A1 (fr) 2008-09-11 2010-03-18 F. Hoffmann-La Roche Ag Nouveaux dérivés de benzimidazole
WO2010034649A1 (fr) 2008-09-25 2010-04-01 F. Hoffmann-La Roche Ag Indazole 2,3-substitué ou 4,5,6,7-tétrahydro-indazoles en tant que modulateurs de fxr contre la dyslipidémie et les maladies associées
WO2010034657A1 (fr) 2008-09-25 2010-04-01 F. Hoffmann-La Roche Ag Dérivés de 3-amino-indazole ou de 3-amino-4,5,6,7-tétrahydro-indazole
WO2011020615A1 (fr) 2009-08-19 2011-02-24 Phenex Pharmaceuticals Ag Nouveaux composés se liant au fxr (nr1 h4) et modulant son activité

Non-Patent Citations (67)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1975, MACK PUBLISHING COMPANY
A. A. LEVIN ET AL., NATURE, vol. 355, 1992, pages 359
A. DE GOTTARDI ET AL., DIG. DIS. SCI., vol. 49, 2004, pages 982
A. KIM ET AL., CARCINOGENESIS, vol. 30, 2009, pages 927
A. LORENTZEN ET AL., BMC CANCER, vol. 7, 2007, pages 192
A. M. THOMAS AM ET AL., HEPATOLOGY, vol. 51, 2010, pages 1410
A. PIEPOLI ET AL., BMC MED. GENOMICS, vol. 2, 2009, pages 11
A. VAN DE WINKEL ET AL., HISTOPATHOLOGY, vol. 58, 2011, pages 246
ANSEL: "Introduction to Pharmaceutical Dosage Forms", 1985, pages: 126
B. CARIOUS ET AL., J. BIOL. CHEM., vol. 281, 2006, pages 11039
B. GOODWIN ET AL., MOL. CELL, vol. 6, 2000, pages 517
B.W. KATONA ET AL., J. BIOL. CHEM., vol. 284, 2009, pages 3354
C. DEGIROLAMO ET AL., TRENDS MOL. MED., vol. 17, 2011, pages 564
C. K. GLASS, ENDOCR. REV., vol. 15, 1994, pages 391
C. M. GORMAN ET AL., MOL. CELL. BIOL., vol. 2, 1982, pages 1044
CHOI MIN JUNG ET AL: "Cafestol, a coffee-specific diterpene, induces apoptosis in renal carcinoma Caki cells through down-regulation of anti-apoptotic proteins and Akt phosphorylation", CHEMICO-BIOLOGICAL INTERACTIONS, vol. 190, no. 2-3, April 2011 (2011-04-01), pages 102 - 108, XP002669042, ISSN: 0009-2797 *
D. C. LEE ET AL., CANCER RES., vol. 68, 2008, pages 4210
D. CHU ET AL., MOL. CANCER THER., vol. 10, 2011, pages 47
D. J. PARKS ET AL., SCIENCE, vol. 284, 1999, pages 1365
D. L. H. SMITH ET AL., CARCINOGENESIS, vol. 31, 2010, pages 1100
F. YANG ET AL., CANCER RES., vol. 67, 2007, pages 863
FIORUCCI STEFANO ET AL: "THE FXR-AGONIST, 6 -ETHYL-CHENODEOXYCHOLIC ACID (6-ECDCA), PROTECTS AGAINST ESTROGEN-INDUCED CHOLESTASIS IN RATS", GASTROENTEROLOGY, ELSEVIER, PHILADELPHIA, PA, vol. 124, no. 4, suppl. 1, 1 April 2003 (2003-04-01), XP009125043, ISSN: 0016-5085, [retrieved on 20060906], DOI: 10.1016/S0016-5085(03)83528-X *
G. ZHOU ET AL., MOL. ENDOCRINOL., vol. 12, 1998, pages 1594
H. K. CHONG ET AL., NUCLEIC ACIDS RES., vol. 38, 2010, pages 6007
H. KUROSU ET AL., J. BIOL. CHEM., vol. 282, 2007, pages 26687
H. ZHAO ET AL., BMC CANCER, vol. 8, 2008, pages 303
HOROWITZ ET AL: "Novel cytotoxic agents from an unexpected source: Bile acids and ovarian tumor apoptosis", GYNECOLOGIC ONCOLOGY, ACADEMIC PRESS, LONDON, GB, vol. 107, no. 2, 1 November 2007 (2007-11-01), pages 344 - 349, XP022350668, ISSN: 0090-8258, DOI: 10.1016/J.YGYNO.2007.07.072 *
I. BRONSTEIN ET AL., J. CHEMILUM. BIOLUM., vol. 4, 1989, pages 99
I. KIM ET AL., CARCINOGENESIS, vol. 28, 2007, pages 940
J. BERGER ET AL., GENE, vol. 66, 1988, pages 1
J. C. OWICKI, J. BIOMOL. SCREEN., vol. 5, 2000, pages 297
J. F. GLICKMAN ET AL., J. BIOMOL. SCREEN., vol. 7, 2002, pages 3
J. M. LEHMANN ET AL., J. BIOL CHEM., vol. 272, 1997, pages 3137
J. W. CARPENTER ET AL., METHODS MOL. BIOL., vol. 190, 2002, pages 31
J. ZHENG ET AL., ASIAN PAC. J. CANCER PREV., vol. 11, 2010, pages 1817
J. ZHENG ET AL., BMC CANCER, vol. 11, 2011, pages 251
K. MA ET AL., J. CLIN. INVEST., vol. 116, 2006, pages 1102
K.S. TAO ET AL., MED. HYPOTHESES, vol. 71, 2008, pages 730
KATONA BRYSON W ET AL: "Characterization of Enantiomeric Bile Acid-induced Apoptosis in Colon Cancer Cell Lines", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 284, no. 5, January 2009 (2009-01-01), pages 3354 - 3364, XP002669040, ISSN: 0021-9258 *
LORENTZEN ANDERS ET AL: "Expression profile of the N-myc Downstream Regulated Gene 2 (NDRG2) in human cancers with focus on breast cancer", BMC CANCER, BIOMED CENTRAL, LONDON, GB, vol. 11, no. 1, 12 January 2011 (2011-01-12), pages 14, XP021087220, ISSN: 1471-2407, DOI: 10.1186/1471-2407-11-14 *
M. L: CRAWLEY, EXPERT OPIN. THER. PAT., vol. 20, 2010, pages 1047
M. TEPEL ET AL., INT. J. CANCER., vol. 123, 2008, pages 2080
M.J. CHOI ET AL., CHEM.-BIOL. INTERACT., vol. 190, 2011, pages 102
M.L. RICKETTS ET AL., MOL. ENDOCRINOL., vol. 21, 2007, pages 1603
N. HE ET AL., GASTROENTEROLOGY, vol. 134, 2008, pages 793
N.S. HOROWITZ ET AL., GYNECOL. ONCOL., vol. 107, 2007, pages 344
PELLICCIARI ROBERTO ET AL: "Bile acid derivatives as ligands of the farnesoid X receptor. Synthesis, evaluation, and structure-activity relationship of a series of body and side chain modified analogues of chenodeoxycholic acid", JOURNAL OF MEDICINAL CHEMISTRY, vol. 47, no. 18, 26 August 2004 (2004-08-26), pages 4559 - 4569, XP002669041, ISSN: 0022-2623 *
R. A. HEYMAN ET AL., CELL, vol. 68, 1992, pages 397
R. C. BUIJSMAN ET AL., CURR. MED. CHEM., vol. 12, 2005, pages 1017
R. M. EVANS, SCIENCE, vol. 240, 1988, pages 889
R. M. HUBER ET AL., GENE, vol. 290, 2002, pages 35
R. MUKHERJEE ET AL., J. STEROID BIOCHEM. MOL. BIOL., vol. 81, 2002, pages 217
R. PELLICIARI ET AL., J. MED. CHEM., vol. 47, 2004, pages 4559
R. R. MARAN ET AL., J. PHARMACOL. EXP. THER., vol. 328, 2009, pages 469
R. Y. TSIEN, ANNU. REV. BIOCHEM., vol. 67, 1998, pages 509
S. FIORUCCI ET AL., GASTROENTEROL, vol. 124, no. 4, 2003, pages A6981
S. FIORUCCI ET AL., J. PHARMACOL. EXP. THER., vol. 314, 2005, pages 584
S. MODICA ET AL., CANCER RES., vol. 68, 2008, pages 9589
S. R. KAIN, METHODS MOL. BIOL., vol. 63, 1997, pages 49
S. ZHANG ET AL., J. HEPATOL., vol. 51, 2009, pages 380
T. T. LU ET AL., MOL. CELL, vol. 6, 2000, pages 507
TAO K S ET AL: "The multifaceted mechanisms for coffee's anti-tumorigenic effect on liver", MEDICAL HYPOTHESES, EDEN PRESS, PENRITH, US, vol. 71, no. 5, 1 November 2008 (2008-11-01), pages 730 - 736, XP025470078, ISSN: 0306-9877, [retrieved on 20080812], DOI: 10.1016/J.MEHY.2008.06.026 *
Y. D. WANG ET AL., CELL RES., vol. 18, 2008, pages 1087
Y. HONG ET AL., CLIN. CANCER RES., vol. 13, 2007, pages 1107
Y. J. KIM ET AL., CARCINOGENESIS, vol. 30, 2009, pages 598
Y. ZHANG ET AL., HEPATOLOGY, vol. 48, 2008, pages 289
Y. ZHANG ET AL., PROC. NATL. ACAD. SCI. USA, vol. 103, 2006, pages 1006

Cited By (86)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE48286E1 (en) 2001-03-12 2020-10-27 Intercept Pharmaceuticals, Inc. Steroids as agonists for FXR
US10485795B2 (en) 2011-07-13 2019-11-26 Gilead Sciences, Inc. FXR (NR1H4) binding and activity modulating compounds
US10220027B2 (en) 2011-07-13 2019-03-05 Gilead Sciences, Inc. FXR (NR1H4) binding and activity modulating compounds
EP3711762A1 (fr) 2013-09-11 2020-09-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pharmaceutiques pour le traitement de l'infection par le virus de l'hépatite b chronique
US10544185B2 (en) * 2015-02-16 2020-01-28 Suzhou Zelgen Biopharmaceuticals Co., Ltd. Deuterated chenodeoxycholic acid derivative and pharmaceutical composition comprising compound thereof
US20180030083A1 (en) * 2015-02-16 2018-02-01 Suzhou Zelgen Biopharmaceuticals Co., Ltd. Deuterated chenodeoxycholic acid derivative and pharmaceutical composition comprising compound thereof
JP2018505220A (ja) * 2015-02-16 2018-02-22 ▲蘇▼州▲澤▼▲ジン▼生物制▲薬▼有限公司 重水素化ケノデオキシコール酸誘導体およびこの化合物を含む薬物組成物
US11958879B2 (en) 2015-03-31 2024-04-16 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
US20180148470A1 (en) * 2015-04-28 2018-05-31 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Cholic acid derivative, and preparation method and medical use thereof
CN109071470A (zh) * 2016-01-26 2018-12-21 江苏豪森药业集团有限公司 Fxr激动剂及其制备方法和应用
CN109071470B (zh) * 2016-01-26 2021-10-15 江苏豪森药业集团有限公司 Fxr激动剂及其制备方法和应用
WO2017128896A1 (fr) * 2016-01-26 2017-08-03 江苏豪森药业集团有限公司 Agoniste de fxr et son procédé de préparation et utilisation associée
CN106995416A (zh) * 2016-01-26 2017-08-01 上海翰森生物医药科技有限公司 Fxr激动剂及其制备方法和应用
WO2017147047A1 (fr) * 2016-02-22 2017-08-31 Alios Biopharma, Inc. Modulateurs de fxr et leurs procédés d'utilisation
US10369160B2 (en) 2016-04-13 2019-08-06 Intercept Pharmaceuticals, Inc. Methods of treating cancer
CN109071452A (zh) * 2016-04-13 2018-12-21 英特塞普特医药品公司 治疗癌症的方法
IL262342B (en) * 2016-04-13 2022-08-01 Intercept Pharmaceuticals Inc An fxr agonist for use as a medicament for the treatment or prevention of hepatocellular carcinoma
WO2017180577A1 (fr) * 2016-04-13 2017-10-19 Intercept Pharmaceuticals, Inc. Procédés de traitement du cancer
AU2017249226B2 (en) * 2016-04-13 2021-07-15 Intercept Pharmaceuticals, Inc. Methods of treating cancer
JP2019511550A (ja) * 2016-04-13 2019-04-25 インターセプト ファーマシューティカルズ， インコーポレイテッド 癌を治療する方法
US20190298742A1 (en) * 2016-04-13 2019-10-03 Intercept Pharmaceuticals, Inc. Methods of treating cancer
US10080742B2 (en) 2016-04-26 2018-09-25 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
US10080741B2 (en) 2016-04-26 2018-09-25 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
US10080743B2 (en) 2016-04-26 2018-09-25 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
US10144729B2 (en) 2016-05-18 2018-12-04 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
US10149835B2 (en) 2016-05-18 2018-12-11 Elmore Patent Law Group, P.C. Isoxazole derivatives as FXR agonists and methods of use thereof
US10138228B2 (en) 2016-05-18 2018-11-27 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use therof
US10774054B2 (en) 2016-06-13 2020-09-15 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10981881B2 (en) 2016-06-13 2021-04-20 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10329286B2 (en) 2016-06-13 2019-06-25 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
EP4534536A1 (fr) * 2016-06-13 2025-04-09 Gilead Sciences, Inc. Composés modulateurs de fxr (nr1h4)
EP3257847A1 (fr) * 2016-06-13 2017-12-20 Gilead Sciences, Inc. Modulateurs du fxr (nr1h4)
JP2019517569A (ja) * 2016-06-13 2019-06-24 ギリアード サイエンシーズ， インコーポレイテッド Ｆｘｒ（ｎｒ１ｈ４）調節化合物
CN109476636B (zh) * 2016-06-13 2024-01-09 吉利德科学公司 调节fxr(nr1h4)的化合物
EP3587412A1 (fr) * 2016-06-13 2020-01-01 Gilead Sciences, Inc. Composés de modulation fxr (nr1h4)
AU2017284109B2 (en) * 2016-06-13 2020-01-23 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
JP2019517568A (ja) * 2016-06-13 2019-06-24 ギリアード サイエンシーズ， インコーポレイテッド Ｆｘｒ（ｎｒ１ｈ４）調節化合物
US11739065B2 (en) 2016-06-13 2023-08-29 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
EP4089072A1 (fr) * 2016-06-13 2022-11-16 Gilead Sciences, Inc. Composés de modulation fxr (nr1h4)
WO2017218330A1 (fr) * 2016-06-13 2017-12-21 Gilead Sciences, Inc. Composés modulant le fxr (nr1h4)
JP7057460B2 (ja) 2016-06-13 2022-04-19 ギリアード サイエンシーズ， インコーポレイテッド Ｆｘｒ（ｎｒ１ｈ４）調節化合物
US11247986B2 (en) 2016-06-13 2022-02-15 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
CN109476636A (zh) * 2016-06-13 2019-03-15 吉利德科学公司 调节fxr(nr1h4)的化合物
CN109311849A (zh) * 2016-06-13 2019-02-05 吉利德科学公司 调节fxr(nr1h4)的化合物
KR102361996B1 (ko) 2016-06-13 2022-02-14 길리애드 사이언시즈, 인코포레이티드 Fxr (nr1h4) 조정 화합물
IL263493A (en) * 2016-06-13 2019-01-31 Gilead Sciences Inc Modulating compounds (fxr (nr1h4)
JP2021113198A (ja) * 2016-06-13 2021-08-05 ギリアード サイエンシーズ， インコーポレイテッド Ｆｘｒ（ｎｒ１ｈ４）調節化合物
KR20210088748A (ko) * 2016-06-13 2021-07-14 길리애드 사이언시즈, 인코포레이티드 Fxr (nr1h4) 조정 화합물
US10421730B2 (en) 2016-06-13 2019-09-24 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
EA037694B1 (ru) * 2016-06-13 2021-05-04 Джилид Сайэнс, Инк. Соединения, модулирующие fxr (nr1h4)
CN109311849B (zh) * 2016-06-13 2021-02-26 吉利德科学公司 调节fxr(nr1h4)的化合物
US11034684B2 (en) 2016-10-04 2021-06-15 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
US10450306B2 (en) 2016-10-04 2019-10-22 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
JP2019535811A (ja) * 2016-10-22 2019-12-12 へパジーン セラピューティクス インコーポレイテッド 複素環式ｆｘｒモジュレーター
JP7065107B2 (ja) 2016-10-22 2022-05-11 へパジーン セラピューティクス （エイチケイ） リミテッド 複素環式ｆｘｒモジュレーター
US10597391B2 (en) 2016-10-26 2020-03-24 Enanta Pharmaceuticals, Inc. Urea-containing isoxazole derivatives as FXR agonists and methods of use thereof
JP2020510009A (ja) * 2017-03-07 2020-04-02 インターセプト ファーマシューティカルズ， インコーポレイテッド 癌を処置する方法
US20180256600A1 (en) * 2017-03-07 2018-09-13 Intercept Pharmaceuticals, Inc. Methods of treating cancer
EP3592357A4 (fr) * 2017-03-07 2021-01-13 Intercept Pharmaceuticals, Inc. Méthodes de traitement du cancer
JP7042836B2 (ja) 2017-03-07 2022-03-28 インターセプト ファーマシューティカルズ， インコーポレイテッド 癌を処置する方法
CN110430882A (zh) * 2017-03-07 2019-11-08 英特塞普特医药品公司 治疗癌症的方法
US11833150B2 (en) 2017-03-28 2023-12-05 Gilead Sciences, Inc. Methods of treating liver disease
CN110944635A (zh) * 2017-03-30 2020-03-31 国家医疗保健研究所 用于减少附加体病毒的持久性和表达的方法和药物组合物
WO2018178260A1 (fr) 2017-03-30 2018-10-04 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour réduire la persistance et l'expression des virus épisomiques
US10988449B2 (en) 2017-04-12 2021-04-27 Il Dong Pharmaceutical Co., Ltd. Isoxazole derivatives as nuclear receptor agonists and uses thereof
EP3658150A4 (fr) * 2017-07-24 2021-03-31 Intercept Pharmaceuticals, Inc. Dérivés d'acide biliaire à marquage isotopique
US10689391B2 (en) 2017-12-12 2020-06-23 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
US10829486B2 (en) 2018-02-14 2020-11-10 Enanta Pharmacueticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
US11225473B2 (en) 2019-01-15 2022-01-18 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US12102625B2 (en) 2019-02-19 2024-10-01 Gilead Sciences, Inc. Solid forms of FXR agonists
US11524005B2 (en) 2019-02-19 2022-12-13 Gilead Sciences, Inc. Solid forms of FXR agonists
WO2020198576A1 (fr) * 2019-03-28 2020-10-01 The Board Of Trustees Of The University Of Illinois Procédés de modulation de lymphocytes t régulateurs
US11555032B2 (en) 2019-05-13 2023-01-17 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
WO2021009332A1 (fr) 2019-07-18 2021-01-21 Enyo Pharma Procédé pour diminuer les effets secondaires de l'interféron
CN112341514B (zh) * 2019-08-06 2023-11-21 杜心赟 脱氧胆酸类化合物、药物组合物及其用途
EP4011899A4 (fr) * 2019-08-06 2022-09-28 Huang, Qiang Composés d'acide désoxycholique, compositions pharmaceutiques et leurs utilisations
CN112341514A (zh) * 2019-08-06 2021-02-09 杜心赟 脱氧胆酸类化合物、药物组合物及其用途
WO2021144330A1 (fr) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'agonistes de fxr pour traiter une infection par le virus de l'hépatite d
CN115666528A (zh) * 2020-03-18 2023-01-31 梅塔科林公司 法尼醇x受体激动剂的制剂
CN111413447A (zh) * 2020-04-09 2020-07-14 郑州大学第一附属医院 鹅去氧胆酸或/和牛磺酸鹅去氧胆酸在胆管癌诊断方面的应用
WO2022134146A1 (fr) * 2020-12-22 2022-06-30 江苏天士力帝益药业有限公司 Nouvel agoniste de fxr ayant une structure pyrazine, ainsi que procédé de préparation et utilisation
CN114656460A (zh) * 2020-12-22 2022-06-24 江苏天士力帝益药业有限公司 一种新型吡嗪结构fxr激动剂、制备方法及应用
CN114656460B (zh) * 2020-12-22 2025-01-10 江苏天士力帝益药业有限公司 一种新型吡嗪结构fxr激动剂、制备方法及应用
WO2022152770A1 (fr) 2021-01-14 2022-07-21 Enyo Pharma Effet synergique d'un agoniste de fxr et d'ifn pour le traitement d'une infection par le virus de l'hépatite b
WO2022229302A1 (fr) 2021-04-28 2022-11-03 Enyo Pharma Potentialisation forte d'effets d'agonistes de tlr3 à l'aide d'agonistes de fxr en tant que traitement combiné
CN118846078A (zh) * 2024-07-02 2024-10-29 中国人民解放军空军军医大学 Ndrg2基因联合分子靶向抑制剂在制备肾细胞癌治疗药物中的应用

Similar Documents

Publication Publication Date Title
WO2013037482A1 (fr) Agonistes du récepteur du farnésoïde x pour le traitement et la prévention du cancer
Sun et al. The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer
Wang et al. LncRNA SNHG7 promotes the proliferation and inhibits apoptosis of gastric cancer cells by repressing the P15 and P16 expression.
Tao et al. Modeling a human hepatocellular carcinoma subset in mice through coexpression of met and point‐mutant β‐catenin
Shafi et al. Androgen receptors in hormone-dependent and castration-resistant prostate cancer
Gallot et al. Myostatin gene inactivation prevents skeletal muscle wasting in cancer
Uppal et al. Activation of LXRs prevents bile acid toxicity and cholestasis in female mice
Li et al. The orphan nuclear receptor EAR2 is overexpressed in colorectal cancer and it regulates survivability of colon cancer cells
Leung et al. NRF2/SHH signaling cascade promotes tumor-initiating cell lineage and drug resistance in hepatocellular carcinoma
US11596642B2 (en) Therapeutic treatment of breast cancer based on c-MAF status
CN105636594A (zh) 使用雄激素靶向疗法用于治疗肿瘤性疾病的生物标记物
Lim et al. Ligand-independent and tissue-selective androgen receptor inhibition by pyrvinium
Miyamoto et al. Nuclear hormone receptor signals as new therapeutic targets for urothelial carcinoma
BR112014025269B1 (pt) Método in vitro para predizer uma metástase óssea de um câncer de mama triplo negativo e o resultado clínico de um paciente sofrendo do referido câncer, bem como método in vitro para a concepção de uma terapia personalizada e para classificar amostras
AU2017229481A1 (en) 3-desoxy derivative and pharmaceutical compositions thereof
AU2010310477A1 (en) Method for treating androgen receptor positive cancers
WO2012142208A1 (fr) Inhibiteurs d'akr1c3 bifonctionnels/modulateurs des récepteurs aux androgènes, et leurs procédés d'utilisation
US20080299118A1 (en) FXR Agonists for the Treatment of Malignancies
Wu et al. MicroRNA-145 mediates the formation of angiotensin II-induced murine abdominal aortic aneurysm
WO2014117697A1 (fr) Application d'un microarn ou d'un inhibiteur de celui-ci dans la régulation et le contrôle du métabolisme des lipides
Innamorati et al. The curious case of Gαs gain-of-function in neoplasia
Wang et al. Loss of hepatic FTCD promotes lipid accumulation and hepatocarcinogenesis by upregulating PPARγ and SREBP2
Powell et al. Mouse strains for prostate tumorigenesis based on genes altered in human prostate cancer
Chang et al. Loss of hepatic miR-194 promotes liver regeneration and protects from acetaminophen-induced acute liver injury
Sroka et al. Differential localization of MT1‐MMP in human prostate cancer tissue: role of IGF‐1R in MT1‐MMP expression

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12761546

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12761546

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载