Glucocorticoid Receptor (GR) Agonist | BI 653048

Target protein: 
GR
Probe Name: 
BI 653048
MOLECULAR WEIGHT [DA]: 
515.5
In stock: 
857

Chemical structure

2D structure of BI 653048

Highlights

BI 653048 is a “dissociated” GR agonist (displaying different transcriptional regulatory profiles between gene transrepression and transactivation) with selectivity against other nuclear receptors (MR, PR) and improved drug-like properties like reduced CYP-inhibition across isoforms and reduced affinity for the hERG ion channel. For unkown reasons, the compound shows species selectivity with reduced mouse functional transrepression potency and is not suitable for evaluation in standard preclinical in vivo mouse models.

3D structure of BI 653048

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Target information

Cortisol and the related cortisone and corticosterone are steroid hormones that are referred to as glucocorticoids (GCs) and bind to the glucocorticoid receptor (GR), which belongs to a large family of transcription factors, the superfamily of nuclear hormone receptors. GCs play an important role in the regulation of the immune system and therefore are widely used in the treatment of inflammatory and immune diseases such as rheumatoid arthritis, asthma, allergy, and sepsis. Synthetic GCs, which differ from cortisol in their pharmacokinetics and pharmacodynamics, have been created with dexamethasone and prednisolone being among the most extensively used anti-inflammatory agents. However, because of harmful dose-limiting side effects and the occurrence of glucocorticoid resistance, the use of these drugs is limited. Side effects include weight gain, hypertension, muscle weakness, skin thinning, diabetes, and the most troublesome GC-induced osteoporosis leading to a weakening of the trabecular bone, which causes a significant increase in the risk of spine, hip, and rib fractures. Upon binding of GCs to GR, a conformational change is provoked leading to the release of GR from the chaperone complexes and unmasking of nuclear localization signals followed by translocation of the GR–ligand complex to the nucleus. There, it is thought to directly and indirectly induce the expression of a few hundred genes, which is largely cell-type specific. The precise molecular mechanism is highly complex and, despite an impressive amount of research, still only partially understood. However, a simplistic hypothesis, which is based on a series of experiments, has become broadly accepted among researchers aiming at GCs with reduced side effects. This hypothesis attributes the anti-inflammatory effects of GCs to the inhibition of gene transcription, referred to as transrepression, while making the activation of transcription, called transactivation, responsible for the majority of side effects. Mechanistically it was rationalized that transrepression involves the GR–ligand complex indirectly in the transcription process through its interaction in a monomeric form with transcription factors such as NF-κB and AP-1 resulting in the down-regulation of key cytokine inflammatory mediators such as TNF-α, IL-1, IL-2, and IL-6. The transactivation pathway directly involves homodimers of GR recognizing GR response elements (GREs) on the DNA resulting in the transcription of genes. While this hypothesis is experimentally poorly supported and partially even contradicted, it served as an appealing working model for drug discovery programs over the past decade. Several companies have invested intense research in the quest of identifying functionally selective, so-called “dissociated” synthetic glucocorticoids with the goal of offering a therapeutic advantage over currently marketed GCs.1

Human glucocorticoid receptor with bound agonist (PDB code: 3k23)

Human glucocorticoid receptor with bound agonist (PDB code: 3k23)

In vitro Activity

In vitro activity table

Probe name / Negative control

BI 653048

BI-3047

MW [Da]

515.52

515.52

GR (IC50[nM]a

55

>2000

IL-6 IC50[nM]a

23

-

IL-6 (IC50) max. eff. [%]a,b

88

-

MMTV max. eff. [%]a,b

33

-

OC max. eff. [%]a,b

39

-

hERG (IC50)a

>30

-

CP 1A2 [µM]

>50

-

CYP 2D6 [µM]

41

-

CYP 2C9 [µM]

12

4.2

CYP 2C19[µM]

9

18

CYP 3A4 [µM]

8

-

a Assay conditions can be downloaded free of charge from pubs.acs.org.

b Maximum efficacy at the highest tested concentration compared to dexamethasone, defined at 100%; maximum concentration tested is 2 μM.

In vitro DMPK parameters

In vitro DMPK parameters table

Probe name

BI 653048

Solubility @ pH 6.8 [µg/ml]

5

HLM[%QH]

11

Plasma protein binding human [%] rat/human

91.8

96.1

In vivo DMPK parameters

In vivo DMPK parameters table

Probe name

BI 653048

Rat PK t1/2[h]

4.2

In vivo pharmacology

Species selectivity of this subseries of compounds precluded a pharmacological evaluation of BI 653048 in standard preclinical in vivo mouse models. Translation of in vitro dissociation markers to preclinical in vivo mouse models had been previously established with tool compounds.2

BI 653048 was tested in a 9-day type II collagen-induced arthritis model in rats at 3, 10, and 30 mg/kg qd po in 30% cremophor to guide human efficacious concentration projections. Animals treated with the low dose (3 mg/kg) of BI 653048 had nonsignificant decreases for all measured histology parameters (ankle inflammation, pannus formation, cartilage damage, and bone resorption).1

Middose (10 mg/kg) animals had significantly decreased pannus and bone resorption (33%) as well as summed scores (27%), while all parameters were significantly decreased (87−96%) in the high dose (30 mg/kg) group. The ED50 value for the summed scores was 14 mg/kg. No side effect related parameters could be evaluated in this shorter duration model 1.

Negative control

MOLECULAR WEIGHT OF NEGATIVE CONTROL [DA]: 
515.5

BI-3047 shows no activity on GR (CR IC50 > 2 µM)

BI-3047, negative control

BI-3047, negative control

Selectivity

Screened against related nuclear receptors (PR, MR, ER, AR): > 100fold selectivity achieved.

A Eurofins-Panlabs® panel was performed and did not give strong hits: %CTRL >75% for all 49 targets tested @ 10 µM. The data can be downloaded from this platform.

Selectivity data available

Probe name

BI 653048

Cerep®

No

Eurofins-Panlabs®

Yes

Invitrogen®

No

DiscoverX®

No

Dundee

No

Download selectivity data: 

reference molecules

For reviews see Reference 3

Summary

BI 653048 is a “dissociated” GR agonist (displaying different transcriptional regulatory profiles between gene transrepression and transactivation) with selectivity for other nuclear receptors (MR, PR) and good drug-like properties.

Supplementary data

References

  1. Optimization of drug-like properties of nonsteroidal glucocorticoid mimetics and identification of a clinical candidate

    Christian Harcken, Doris Riether, Pingrong Liu, Hossein Razavi, Usha Patel, Thomas Lee, Todd Bosanac, Yancey Ward, Mark Ralph, Zhidong Chen, Donald Souza, Richard M. Nelson, Alison Kukulka, Tazmeen N. Fadra-Khan, Ljiljana Zuvela-Jelaska, Mita Patel, David S. Thomson, and Gerald H. Nabozny

    ACS Med Chem Lett. 2014;5:1318-1323.

  2. Identification of Highly Efficacious Glucocorticoid Receptor Agonists with a Potential for Reduced Clinical Bone Side Effects

    Christian Harcken, Doris Riether, Daniel Kuzmich, Pingrong Liu, Raj Betageri, Mark Ralph, Michel Emmanuel, Jonathan T. Reeves, Angela Berry, Donald Souza, Richard M. Nelson, Alison Kukulka, Tazmeen N. Fadra, Ljiljana Zuvela-Jelaska, Roger Dinallo, Jörg Bentzien, Gerald H. Nabozny, and David S. Thomson

    J Med Chem. 2014;57:1583-1598.

  3. Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds

    Nora Sundahl, Jolien Bridelance, Claude Libert, Karolien De Bosscher, Ilse M. Beck

    Pharmacol Ther. 2015;152:28-41