15 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 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.

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 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.

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.

Disclosed herein are antibody-drug-conjugates (ADC) that allow for delivery and release of glucocorticoid receptor modulators into desired tissues. The disclosed ADCs include a peptide that facilitates the release of a glucocorticoid receptor modulator by legumain. The antibody-drug-conjugates are useful as therapeutic agents for treating various autoimmune disorders, inflammatory disorders, and blood cancers. Pharmaceutical compositions which include the ADCs are also disclosed, as are methods of treating autoimmune disorders, inflammatory disorders, and blood cancers by administering a therapeutically effective amount of an antibody-drug-conjugate disclosed herein under conditions effective to treat said disorders.

Applicant discloses methods and compositions for reducing liver fat and for treating fatty liver diseases (e.g., non-alcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) and nonalcoholic cirrhosis; alcohol related fatty liver diseases including, alcohol fatty liver disease (AFL), alcoholic steatohepatitis (ASH), and alcoholic cirrhosis; and liver fibrosis). Significant liver fat reductions were obtained in human patients after only between 30 to 44 days of administration of 600 mg / day or 900 mg / day of the cyclohexyl pyrimidine glucocorticoid receptor modulator miricorilant. Liver fat reductions ranged from 38.5% to 73.8% (magnetic resonance imaging measurements in 4 of 5 patients receiving miricorilant, measured between 16-64 days after cessation of miricorilant administration). A further effect of miricorilant was an increase in liver alanine amino transferase (ALT) and aspartate amino transferase (AST). Mouse studies showed that miricorilant reduced measures of NAFLD, body weight, liver weight, and liver collagen and galectin-3 levels.

Methods and compositions for treating a subject suffering from adrenocortical carcinoma and having excess cortisol are disclosed. The methods provide therapeutic benefits including reduction of ACC tumor load, restoration of T-cell and natural killer (NK) cell signaling pathways, increase in T-cell and NK cell infiltration into the ACC tumor, reduction of neutrophil infiltration into the ACC tumor in the patient, and other therapeutic benefits. The methods include administration of a glucocorticoid receptor modulator (GRM) (which may be a selective glucocorticoid receptor modulator (SGRM)) and an antibody checkpoint inhibitor. In embodiments, the GRM (e.g., a SGRM) is orally administered. The GRM may be a nonsteroidal compound comprising: a fused azadecalin structure; a heteroaryl ketone fused azadecalin structure; or an octahydro fused azadecalin structure.

Combined administration of a selective glucocorticoid receptor modulator (SGRM; e.g., relacorilant or exicorilant) and a cancer therapeutic (e.g., a taxane or antiandrogen) is useful for identifying elevated cortisol activity in patients with cancer or with Cushing's syndrome, and for treating patients with cancer (e.g., ovarian, pancreatic, or prostate cancer). An at least 40% change in RNA levels encoding CDKN1C, TNFRSF17, BRIP1, PDK1, CLEC10A, FPR3, CCR2, LILRB4, or CD86 indicates that the patient with cancer is likely to benefit from the combined treatment (e.g., likely to have longer survival than similar patients not receiving combined treatment). An active SGRM dose is identified where RNA levels encoding CDKN1C, TNFRSF17, BRIP1, or PDK1 decrease, or where RNA levels encoding CLEC10A, FPR3, CCR2, LILRB4, and CD86 increase, by at least 40 %. Changes in RNA levels encoding CLEC10A, FPR3, CCR2, LILRB4, and CD86 identify patients with cancer or with Cushing's having elevated cortisol activity.

The invention provides a biomarker for diagnosing depression and application thereof. Experiments prove the relationship between HPA / corticosterone / glucocorticoid receptor / GNMT / glycine and sarcosine, the HPA / corticosterone and sarcosine are in negative correlation regulation, and the glucocorticoid receptor / GNMT / glycine and sarcosine are in positive correlation regulation. The invention also provides a biomarker capable of effectively diagnosing depression. The biomarker comprises sarcosine, methyl stearate and LysoPE (16: 1 (9Z) / 0: 0) in the exosome. Besides, the depression animal model is constructed by reducing GNMT, and the depression animal model can be used for depression drug screening, efficacy evaluation or diagnosis, and can also be used for researching and revealing the pathogenesis of depression. The invention has important significance on the diagnosis and treatment of depression, and has wide application prospects in clinic.

Disclosed herein are antibody-drug-conjugates (ADC) that allow for delivery and release of glucocorticoid receptor modulators into desired tissues. The disclosed ADCs include a peptide that facilitates the release of a glucocorticoid receptor modulator by legumain. The antibody-drug-conjugates are useful as therapeutic agents for treating various autoimmune disorders, inflammatory disorders, and blood cancers. Pharmaceutical compositions which include the ADCs are also disclosed, as are methods of treating autoimmune disorders, inflammatory disorders, and blood cancers by administering a therapeutically effective amount of an antibody-drug-conjugate disclosed herein under conditions effective to treat said disorders.

The present invention provides methods and compositions for treating cancer (for example, ovarian cancer, fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer, or peritoneal cancer). [Solution] This disclosure relates to intermittent administration of a glucocorticoid receptor modulator for the treatment of ovarian cancer and other cancers.