53 results about "Glucocorticoid receptor" patented technology

Many drugs useful in treating cancer are metabolized by CYP2C8 enzymes, by CYP3A4 enzymes, or both. The effects of concomitant administration of relacorilant and paclitaxel, a drug used to treat cancer that is a substrate for both CYP2C8 and CYP3A4, are disclosed herein.Relacorilant potently inhibited CYP2C8 and CYP3A4 in in vitro tests, indicating that co-administration of relacorilant and paclitaxel would increase paclitaxel plasma exposure more than 5-fold in vivo, requiring significant reductions in paclitaxel doses when co-administering paclitaxel with relacorilant.Surprisingly, paclitaxel plasma exposure increased only by about 80% instead of the expected more than 5-fold increase expected with concomitant relacorilant and paclitaxel administration. Applicant discloses safe methods of co-administering relacorilant and paclitaxel by reducing the dose of paclitaxel to about half the paclitaxel dose used when paclitaxel is administered alone. Relacorilant and such reduced doses of paclitaxel may be co-administered to treat cancer, e.g., ovarian or pancreatic cancer.

Relacorilant is useful in the treatment of hypercortisolism and cancer. Many drugs useful in treating hypercortisolism or cancer are metabolized by CYP2C9 enzymes. The effects of concomitant administration of relacorilant and a CYP2C9 substrate are disclosed herein.Relacorilant potently inhibited CYP2C9 in an in vitro test, indicating that co-administration of relacorilant and a CYP2C9 substrate would be expected to increase the CYP2C9 substrate plasma exposure more than five-fold in vivo. Significant reductions in CYP2C9 substrate doses would be expected to be required when administered with relacorilant.Surprisingly, no such increase in plasma exposure was seen in human studies. Applicant discloses that relacorilant may be safely co-administered with unmodified doses of a CYP2C9 substrate such as, e.g., tolbutamide, glimepiride, and glipizide. Relacorilant and unmodified doses of CYP2C9 substrate such as tolbutamide, glimepiride, and glipizide may be co-administered to treat hypercortisolism, or may be co-administered to a cancer patient.

Methods and compositions for treating a subject hosting a non-ACTH-secreting pancreatic tumor are disclosed. The methods include administering to the subject a chemotherapeutic agent and a glucocorticoid receptor modulator (GRM), preferably a selective glucocorticoid receptor modulator (SGRM), to reduce the tumor load in the subject. The GRM may be a nonsteroidal GRM, and may be a nonsteroidal SGRM. The non-ACTH-secreting pancreatic tumor may be an exocrine pancreatic tumor.The nonsteroidal SGRM may be a nonsteroidal compound comprising: a fused azadecalin structure; a heteroaryl ketone fused azadecalin structure; or an octahydro fused azadecalin structure. Pharmaceutical compositions comprising a chemotherapeutic agent and a GRM are disclosed. The GRM in such pharmaceutical compositions may be a nonsteroidal GRM, and may be a SGRM, such as a nonsteroidal SGRM. The nonsteroidal SGRM may comprise: a fused azadecalin structure; a heteroaryl ketone fused azadecalin structure; or an octahydro fused azadecalin structure.

The invention provides a method for preparing a pyrimidine cyclohexyl glucocorticoid receptor modulator, a method for preparing an intermediate of the pyrimidine cyclohexyl glucocorticoid receptor modulator, and a thioether compound.

The present disclosure provides an anti-cancer lipid-based composition that kills very aggressive colorectal cancer cells. This composition is a concoction of an anti- cancer agent, 5-Fluorouracil and a glucocorticoid receptor (GR)-targeting cationic lipid delivery system, D1X. The uptake studies of these formulations have showed that formulations with dexamethasone enter into nucleus, bind GRE region and upregulate CYP3a5 gene. The intensity of upregulation is better than liposome without dexamethasone. Same results found in in vivo studies, the D1X5-FU shows better tumor regression and survivability than FOLFOX and FOLFIRI. The biodistribution studies showed that D1X5-FU targets only tumor tissues, not other organs. The pilot studies of tumor regression by other liposomal formulations- D1XLeucovorin, D1XOxaliplatin has showed better tumor regression than FOLFOX and FOLFIRI.

The present invention provides processes for preparing intermediates for heteroaryl-ketone fused azanaphthane glucocorticoid receptor modulators and compositions with low impurity levels.

The present invention relates to compounds according to general formula (I) which act as modulators of the glucocorticoid receptor and can be used in the treatment and / or prophylaxis of disorders which are at least partly mediated by the glucocorticoid receptor.

The present invention provides formulations of (R)-(1-(4-fluorophenyl)-6-((4-trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, and methods for making and using same.

Methods and compositions for treating a patient suffering from Huntington's disease or treating symptoms thereof are disclosed. The methods comprise administering to the patient an effective amount of a heteroaryl ketone fused aza-naphthane glucocorticoid receptor modulator (GRM) or an octahydro fused aza-naphthane GRM. In an embodiment, the GRM is Dargencolan. In some embodiments, the GRM is zaltile blue. In embodiments, the GRM is administered orally. In some embodiments, the GRM is administered daily; in other embodiments, the GRM is administered in a regimen, such as once every day, once every three days, once per week, or other administration regimen. The symptoms of Huntington's disease that can be treated by the methods described herein include, but are not limited to, motor symptoms (e.g., muscle weakness, posture abnormalities, walking difficulty, dysphagia) and neurological or psychological symptoms (e.g., seizure, amnesia, consciousness disorder, impaired verbal ability, delirium, depression, anxiety).

Methods and compositions for treating a subject with adrenocortical carcinoma and hypercortisolism are disclosed. The methods result in a reduction in ACC tumor burden, restoration of T cell signaling pathways and natural killer (NK) cell signaling pathways, increased infiltration of T cells and NK cells into ACC tumors, and decreased infiltration of neutrophils into ACC tumors, among other therapeutic effects. The methods include administering a glucocorticoid receptor modulator (GRM) (which may be a selective glucocorticoid receptor modulator (SGRM)) and an antibody checkpoint inhibitor. In some embodiments, the GRM (e.g., the SGRM) is administered orally. The GRM may be a non-steroidal compound containing a fused azadecalin structure; a heteroaryl ketone-fused azadecalin structure; or an octahydro-fused azadecalin structure.

Methods and compositions for treating a subject hosting a non-ACTH-secreting pancreatic tumor are disclosed. The methods include administering to the subject a chemotherapeutic agent and a glucocorticoid receptor modulator (GRM), preferably a selective glucocorticoid receptor modulator (SGRM), to reduce the tumor load in the subject. The non-ACTH-secreting pancreatic tumor may be an exocrine pancreatic tumor. The GRM may be a nonsteroidal GRM or a nonsteroidal SGRM. The nonsteroidal SGRM may be a nonsteroidal compound comprising: a fused azadecalin structure; a heteroaryl ketone fused azadecalin structure; or an octahydro fused azadecalin structure. Pharmaceutical compositions comprising a chemotherapeutic agent and a GRM are disclosed. The GRM in such pharmaceutical compositions may be a nonsteroidal GRM, and may be a nonsteroidal SGRM. The nonsteroidal SGRM may comprise: a fused azadecalin structure; a heteroaryl ketone fused azadecalin structure; or an octahydro fused azadecalin structure.

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a novel glucocorticoid and a preparation method and application thereof, the novel glucocorticoid comprises a compound of a formula I, an optical isomer of the compound, a medicinal salt of the compound or a solvate of the compound, and the structural formula of the compound of the formula I is shown in the description. The compound provided by the invention has the advantages of high plasma removal rate, short half-life period, low systemic drug exposure and higher target selectivity to a glucocorticoid receptor (GR), and can obviously reduce side effects caused by systemic absorption of a glucocorticoid drug. The compound has remarkable anti-inflammatory activity on animal asthma, uveitis, xerophthalmia, inflammatory bowel disease, psoriasis and the like. The compound provided by the invention has good safety, no abnormal intraocular pressure is detected when the compound is continuously administered to the eyes of guinea pigs, and no obvious abnormal epidermal layer thickness occurs after the compound is continuously administered to the skin of rats.

Provided herein are recombinant adeno-associated virus (rAAV) particles encoding microRNAs targeting the glucocorticoid receptor (GR) pathway, and in particular a microRNA17-92 (miR 17-92) cluster, and genes of interest. The modified genomes of these rAAV particles comprise heterologous nucleic acid sequences encoding microRNA structures. These particles exhibit enhanced transduction efficiencies in mammalian cells. Also provided herein are compositions of nucleic acids encoding the miR 17-92 cluster and nucleic acids encoding a gene of interest. Further provided herein are methods for administering these nucleic acid compositions to enhance transduction efficiencies.

Methods and uses are disclosed for treating an adrenal tumor in a subject suffering from an adrenal tumor to reduce the size or tumor load of the adrenal tumor, prevent its growth, or slow its growth, or reduce or alter its secretion, or induce its degeneration or apoptosis. The novel methods of treatment include the use or administration of an effective amount of a glucocorticoid receptor modulator (GRM) compound having a heteroaryl-ketone fused aza-naphthane structure to a patient suffering from an adrenal tumor. The adrenal tumor may be a benign adrenal tumor. In some embodiments, GRM may be reracolan, which is ((R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl) sulfonyl)-4, 4a, 5, 6, 7, 8-hexahydro-1H-pyrazolo [3, 4-g] isoquinolin-4a-yl) (4-(trifluoromethyl) pyridin-2-yl) methanone). The GRM may be administered orally. The GRM may be administered with a food. The treatment methods can be used before, during or after an adrenal tumor operation, and can also be used without an operation. The use of these therapeutic methods may not adversely affect normal adrenal gland tissue.

The invention relates to compounds according to general formula (I)which act as modulators of the glucocorticoid receptor and can be used in the treatment and / or prophylaxis of disorders which are at least partially mediated by the glucocorticoid receptor.

The present invention belongs to the field of biomedicine technology and discloses a drug that inhibits colorectal cancer metastasis by targeting glucocorticoid receptor GR. The drug that inhibits colorectal cancer metastasis by targeting glucocorticoid receptor GR is 0.1 μM glucocorticoid and / or 0.1 μM belinostat. The present invention verifies the actual effect of small molecule drugs in CRC by in vitro cell invasion experiments and transcriptome sequencing analysis methods, and the effect of combined treatment with glucocorticoid and belinostat on the invasion of CRC cell line HCT116 cells; HCT116 cells are treated with 0.1 μM glucocorticoid and / or 0.1 μM belinostat for 48 hours, stained with 0.1% crystal violet and photographed, eluted with 33% acetic acid, and the absorbance value is detected by a microplate reader at 590 nm. The experimental results of the present invention show that GC promotes CRC cell invasion, and belinostat combined treatment can effectively inhibit the invasive effect caused by GC.

The present invention relates to a Selective Glucocorticoid Receptor Modulator (SEGRM), or a pharmaceutically acceptable salt thereof, for use in the treatment of impaired skin wound healing in a subject, an in vitro method for identifying a subject suffering from impaired skin wound healing to be responsive to the treatment with a Selective Glucocorticoid Receptor Modulator (SEGRM), or a pharmaceutically acceptable salt thereof, and kits and kits-of-part related thereto.

Disclosed are methods and compositions for diagnosing and treating patients suspected of having disorders such as hypercortisolism, metabolic syndrome, prediabetes, diabetes, Cushing's syndrome, Cushing's disease, hyperglycemia secondary to hypercortisolism, liver disease, cardiac disorders, hypertension, blood clotting disorders, cancer, psychological disorders, weight gain, impaired glucose regulation, bone disorders (e.g., osteoporosis), hypogonadism, pseudoacromegaly, pituitary tumors, functional hypercortisolism, ACTH-secreting tumors, peripheral neuropathy, and dyslipidemia. The methods and compositions involve the administration of a heteroaryl-ketone-fused azadecaline glucocorticoid receptor modulator (GRM). A preferred heteroaryl-ketone-fused azadecalin GRM is relacorilant ((R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone). The GRM (e.g., relacorilant) may be administered orally. The GRM (e.g., relacorilant) may be administered orally without food.

A method for preventing and / or treating systemic inflammatory response syndrome (SIRS), the method comprising administration of an agent capable of up-regulating CD73 in combination with a glucocorticoid and / or an agent capable of agonizing the glucocorticoid receptor, wherein an agent capable of up-regulating CD73 and a glucocorticoid and / or an agent capable of agonizing the glucocorticoid receptor are administered sequentially. An agent capable of up-regulating CD73 is administered prior to a glucocorticoid and / or an agent capable of agonizing the glucocorticoid receptor.

The present invention provides methods for preparing 2-amino-6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidin-4(3H)-one and 2-amino-6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidin-4(3H)-one monohydrate, as well as novel intermediate compounds.

Provided is a method for treating a metabolic disorder with GR modulators (e.g., inhibitors).

A method for treating prostate cancer, including castration-resistant prostate cancer and metastatic castration-resistant prostate cancer, is disclosed, comprising administering an effective amount of an androgen receptor (AR) antagonist and an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM). The AR antagonist may be enzalutamide. The SGRM may be an octahydro-fused azadecalin compound, such as an exicholant having the structure ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone. The AR antagonist and the SGRM may be administered once a day or with food. The dose of enzalutamide may be 150 to 200 mg / day, for example, 160 mg / day, and the dose of exicholant may be 100 to 350 mg / day, for example, 240 mg / day, 280 mg / day, or 320 mg / day.

The invention relates to compounds according to general formula (I),which act as modulators of the glucocorticoid receptor and can be used in the treatment and / or prophylaxis of disorders which are at least partially mediated by the glucocorticoid receptor.

The present invention provides formulations of (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, and methods of making and using the same.

The present disclosure relates to compounds, compositions, and methods useful for modulating a glucocorticoid receptor (GR) and for treating diseases and disorders (e.g., autoimmune diseases and inflammatory diseases).

The present invention provides a method for preparing pyrimidine cyclohexylglucocorticoid receptor modulators, a method for preparing intermediates of pyrimidine cyclohexylglucocorticoid receptor modulators, and thioether compounds.

Relacorilant is a selective modulator of the type II glucocorticoid receptor (GR); it may be orally administered. Applicant discloses in vitro studies that show relacorilant to be a potent inhibitor of P-glycoprotein (P-gp). Surprisingly, in vivo studies of co-administration of relacorilant and dabigatran etexilate (a P-gp substrate) showed that relacorilant had minimal-to-no impact on the free and total dabigatran plasma exposures, suggesting that only minimal or no dose adjustments are needed for P-gp substrates upon coadministration with relacorilant. The surprising finding that relacorilant may be safely co-administered with P-gp substrates without need for significant dose adjustment provides improved methods and uses for treatment of such disorders as, for example, hypercortisolism (e.g., Cushing's syndrome, Cushing's Disease), hyperglycemia, hypertension, and a solid tumor in combination with chemotherapy or immunotherapy agents.