Clinical profile of the functionally selective glucocorticoid receptor agonist BI 653048 in healthy male subjects

Harcken, Christian; Scholl, Paul; Nabozny, Gerald H.; Thomson, D. S.; Bianchi, D.

doi:10.1080/13543784.2019.1599859

Cited by 3 publications

(4 citation statements)

References 14 publications

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“…Trifluoromethyl carbinol-derived compounds are an extremely well-profiled nonsteroidal class of GRLs. In the study of Harcken et al (214), a compound named BI653048 was identified. BI653048 is in the SERGA class, which binds with high affinity to the human GR.…”

Section: Bimentioning

confidence: 99%

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Role of FKBP5 and its genetic mutations in stress-induced psychiatric disorders: an opportunity for drug discovery

Malekpour,

Shekouh,

Safavinia

et al. 2023

Front. Psychiatry

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Stress-induced mental health disorders are affecting many people around the world. However, effective drug therapy for curing psychiatric diseases does not occur sufficiently. Many neurotransmitters, hormones, and mechanisms are essential in regulating the body's stress response. One of the most critical components of the stress response system is the hypothalamus-pituitary-adrenal (HPA) axis. The FKBP prolyl isomerase 51 (FKBP51) protein is one of the main negative regulators of the HPA axis. FKBP51 negatively regulates the cortisol effects (the end product of the HPA axis) by inhibiting the interaction between glucocorticoid receptors (GRs) and cortisol, causing reduced transcription of downstream cortisol molecules. By regulating cortisol effects, the FKBP51 protein can indirectly regulate the sensitivity of the HPA axis to stressors. Previous studies have indicated the influence of FKBP5 gene mutations and epigenetic changes in different psychiatric diseases and drug responses and recommended the FKBP51 protein as a drug target and a biomarker for psychological disorders. In this review, we attempted to discuss the effects of the FKBP5 gene, its mutations on different psychiatric diseases, and drugs affecting the FKBP5 gene.

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Section: Bimentioning

confidence: 99%

“…BI653048 is in the SERGA class, which binds with high affinity to the human GR. They revealed that treatment with 200 mg of BI653048 can be associated with a decreased expression of FKBP5 (214).…”

Section: Bimentioning

confidence: 99%

Role of FKBP5 and its genetic mutations in stress-induced psychiatric disorders: an opportunity for drug discovery

Malekpour,

Shekouh,

Safavinia

et al. 2023

Front. Psychiatry

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“…After two decades with intensive programs in big pharma, only few selective ligands are in clinical trials [77], but rarely used in the clinics. Partially, this might be due to the narrow therapeutic windows of these compounds, but also because the regulation of inflammation by steroids is far more complex than just suppression of cytokines and other pro-inflammatory mediators [78][79][80].…”

Section: Accepted Articlementioning

confidence: 99%

A guide to changing paradigms of glucocorticoid receptor function—a model system for genome regulation and physiology

et al. 2021

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Assay for Transposase-Accessible Chromatin using sequencing BRG1: Brahma Related Gene 1 CBG: corticosteroid-binding globulin CBP: CREB (cAMP response element-binding protein) binding protein CDK9: Cyclin-dependent kinase 9 cGR: cytosolic GR ChIP-MS:ChIP coupled to mass-spectrometry ChIP-Seq: chromatin-immuno-precipitation sequencing ChIP: chromatin immunoprecipitation CLP: cecal ligation and puncture COMPASS: complex of proteins associated with Set1 Cre: "causes recombination" CRF: corticotropin release factor CRH: corticotropin releasing hormone (synonymous for CRF) CRISPR/Cas9: clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 DBD: DNA-binding domain dex: dexamethasone DNase-Seq: DNase I hypersensitive sites sequencing DP: double positive DSS: dextran sodium sulfate colitis Dusp1: dual specificity protein phosphatase 1 EGFP: enhanced green fluorescent protein ENU: N-ethyl-N-nitrosourea ER: estrogen receptor FAIRE-Seq: formaldehyde-assisted isolation of regulatory elements sequencing FCS: fluorescence correlation spectroscopy FKBP5: FK506 binding protein 5

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“…However, prednisolone does reduce bone mineral density in dogs and decreases bone formation markers in humans after 1 day ( 71 , 72 ). Indeed, in a phase I clinical trial, BI653048, and prednisolone both caused decreased serum osteocalcin levels ( 26 ). Studies with other SEGRMs also concluded that osteocalcin levels in cellulo do not always reflect in vivo decreases in bone density ( 18 , 26 , 27 , 37 , 38 ), casting doubts on the value of osteocalcin as proxy for the in vivo reduction of bone mineral density.…”

Section: Bottlenecks and Pitfalls Observed In The Pastmentioning

confidence: 99%

Improved Glucocorticoid Receptor Ligands: Fantastic Beasts, but How to Find Them?

2020

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Exogenous glucocorticoids are widely used in the clinic for the treatment of inflammatory disorders and hematological cancers. Unfortunately, their use is associated with debilitating side effects, including hyperglycemia, osteoporosis, mood swings, and weight gain. Despite the continued efforts of pharma as well as academia, the search for so-called selective glucocorticoid receptor modulators (SEGRMs), compounds with strong anti-inflammatory or anti-cancer properties but a reduced number or level of side effects, has had limited success so far. Although monoclonal antibody therapies have been successfully introduced for the treatment of certain disorders (such as anti-TNF for rheumatoid arthritis), glucocorticoids remain the first-in-line option for many other chronic diseases including asthma, multiple sclerosis, and multiple myeloma. This perspective offers our opinion on why a continued search for SEGRMs remains highly relevant in an era where small molecules are sometimes unrightfully considered old-fashioned. Besides a discussion on which bottlenecks and pitfalls might have been overlooked in the past, we elaborate on potential solutions and recent developments that may push future research in the right direction.

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Clinical profile of the functionally selective glucocorticoid receptor agonist BI 653048 in healthy male subjects

Cited by 3 publications

References 14 publications

Role of FKBP5 and its genetic mutations in stress-induced psychiatric disorders: an opportunity for drug discovery

Role of FKBP5 and its genetic mutations in stress-induced psychiatric disorders: an opportunity for drug discovery

A guide to changing paradigms of glucocorticoid receptor function—a model system for genome regulation and physiology

Improved Glucocorticoid Receptor Ligands: Fantastic Beasts, but How to Find Them?

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