79 results about "Glucocorticoid receptor" patented technology

Disclosed are methods and uses for treating a subject having a condition selected from liver disease, Cushing's syndrome or Cushing's disease, cancer, infection, inflammation, cardiovascular, endocrine or kidney disease, and combinations thereof, or other disease that may thus be administered a drug that may cause hepatotoxicity, the methods and uses having no adverse effects on the liver. The liver diseases comprise fatty liver diseases, high-level liver enzyme can be effectively reduced, and good safety is achieved. The methods and uses include administering to a subject an effective amount of a selective non-steroidal glucocorticoid receptor modulator, such as relacan, including methods and uses for use in combination with other drugs, without adversely affecting liver enzyme levels or liver function. In embodiments, another drug may be a drug that may cause hepatotoxicity, such as a drug that inhibits the CYP3A enzyme, such as itraconazole or ketoconazole.

An application method of Prevotella copri includes: applying thePrevotella copri in preventing and treating the ADHD. The Prevotella copri is applied in an effective therapeutic amount to achieve treating the ADHD, and a strain number of the Prevotella copri is JCM 13464=DSM 18205. It is indicated through animal experiments that the Prevotella copri can significantly improve hyperactive behavior, spontaneous activity levels and impulsive behavior hyperactivity. A further experimental exploration finds that the Prevotella copri can significantly increase levels of adrenocorticotropic hormone and cortisol in serum, improve neuroendocrine system dysfunction, and significantly increase gene expressions of glucocorticoid receptor (Nr3c1) and mineralocorticoid receptor (Nr3c2), thereby alleviating ADHD social dysfunction, which provides a theoretical basis for application prospects of probiotics in alleviating the ADHD.

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.

This invention provides a method that combines a checkpoint inhibitor and a glucocorticoid receptor modulator to treat cancer, e.g., a checkpoint inhibitor sensitive 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 cancer (e.g., ovarian, fallopian tube, uterine, cervical, vaginal, vulvar, or peritoneal cancer) are disclosed. The methods include intermittent administration of a glucocorticoid receptor modulator (GRM), such as a non-steroidal GRM (e.g., relacorilant), which may be orally administered, along with a cancer chemotherapy agent (such as, e.g., bevacizumab) to the patient. The GRM may be administered: at intervals separated by at least one day without GRM administration; by a schedule linked to the cancer chemotherapy schedule (e.g., a weekly chemotherapy regimen); the day of, or the day before, or the day after, chemotherapy administration; by combinations thereof; and / or on other days. Ovarian cancer patients receiving intermittent relacorilant administration along with nab-paclitaxel administration had improved overall survival, improved progression free survival, improved duration of response, and other benefits as compared to patients not receiving relacorilant while receiving nab-paclitaxel.

Provided is a method and a medicament for treating amyotrophic lateral sclerosis (ALS) in a subject in need thereof, comprising administering to the subject an effective amount of one or more active agents selected from the group consisting of a retinoic acid receptor alpha (RARα) agonist, a voltage-gated potassium channel (KCNB2) inhibitor, an adrenergic receptor α2B (ADRA2B) antagonist, a DNA methyltransferase 3 alpha (DNMT3A) antagonist, an insulin like growth factor 1 receptor (IGF1R) inhibitor, a mitogen-activated protein kinase 1 (MAPK1) inhibitor, a nitric oxide synthase 1 (NOS1) inhibitor, a glucocorticoid receptors (NR3C1) antagonist, and a peptidylprolyl Isomerase A (PPIA) antagonist.

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.

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 present invention provides methods of preparing heteroaryl-ketone fused azanaphthane glucocorticoid receptor modulators, as well as compositions having low impurity levels.

The present invention provides octahydro fused azadecalin compounds and methods of using the compounds as glucocorticoid receptor modulators.

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 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 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.

The present invention discloses a compound of formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, a pharmaceutical composition and use. The compound of formula I provided by the present invention has a good therapeutic effect on diseases mediated by glucocorticoid receptor disorders, such as asthma, chronic obstructive pulmonary disease, etc.

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 for treating, identifying and localizing tumors expressing somatostatin receptors (SRs), including methods of enhancing the efficacy of imaging techniques by administration of a heteroaryl-ketone fused azadecalin glucocorticoid receptor modulator (HKGRM) effective to increase SR expression in tumors. HKGRM administration for enhancing SR-based tumor imaging and treating neuroendocrine tumors. HKGRM and somatostatin or somatostatin analog combination therapy for treating and enhancing SR-based tumor imaging.

The present invention provides methods of preparing heteroaryl-ketone fused azadecalin glucocorticoid receptor modulators, and compositions having low impurity levels.

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.

The present invention provides methods of preparing pyrimidine cyclohexyl glucocorticoid receptor modulators, methods of preparing intermediates of pyrimidine cyclohexyl glucocorticoid receptor modulators, and pyridinium compounds.

The present invention provides crystalline forms of (E)-6-(4-Phenylcyclohexyl)-5-(3-trifluoromethylbenzyl)-1H-pyrimidine-2,4-dione, and methods of making and using the same.

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.

The invention relates to the technical field of plant genetic engineering, in particular to an expression vector containing a dexamethasone induction system and application of the expression vector in tomato fruit development. The expression vector provided by the invention comprises a glucocorticoid receptor induction system and a target gene loaded into the glucocorticoid receptor induction system, wherein the target gene comprises at least one of an SlNAM2 gene and an SlNAM3 gene. The expression vector can be used for constructing a transgenic tomato plant, and gene expression in tomato fruits can be accurately regulated and controlled through induction, so that the quality of the tomato fruits can be well improved. The process has small influence on the growth of the whole tomato plant, can realize specific accurate regulation and control on the tomato fruit, and is beneficial to industrialization of tomato fruit quality regulation and control.