The 70th Anniversary of Glucocorticoids in Rheumatic Diseases

The Second Youth of an Old Friend

Yannick Palmowski; Thomas Buttgereit; Frank Buttgereit


Rheumatology. 2019;58(4):580-587. 

In This Article

Dissociated Agonists of the GC Receptor

In order to understand the driving force for the development of GC receptor agonists, it is important to have an idea of how the GC receptor helps to mediate the effects of GCs in our body. After GCs pass the plasma membrane and enter the cytosol, they bind to the cytosolic GC receptor (cGR), forming a GC–cGR complex. Subsequently, two different processes take place. First, the activated GC–cGR complex is translocated to the nucleus, where it binds to DNA-binding sites and induces the transcription and translation of specific proteins. This process is often referred to as transactivation. Second, the GC–cGR complex can also inhibit the synthesis of other proteins, mainly by interaction with transcription factors, which is called transrepression. A widely accepted hypothesis states that transrepression is primarily responsible for the desired anti-inflammatory effects (e.g. by reducing the synthesis of pro-inflammatory cytokines like IL-6 or TNF-α), while undesired effects like hyperglycaemia are the result of transactivation (e.g. by inducing enzymes involved in gluconeogenesis).[54–56] However, it should be noted that this view is highly simplistic and has recently been called into question, as transactivation is also responsible for the induction of some important anti-inflammatory proteins.[57] Still, this hypothesis has been the basis for the development of a number of new drugs, which are called dissociated agonists of the GC receptor, selective GC receptor agonists or selective GC receptor modulators. The underlying idea of these substances is to achieve a receptor conformation that favours transrepression over transactivation, resulting in preserved anti-inflammatory capacities and reduced adverse effects. Recent examples of such agents are the compounds R-18 and R-21, which have already demonstrated good anti-inflammatory capacities in a murine model of RA (collagen-induced arthritis). At the same time, they showed reduced detrimental effects on bone structure as well as relevant parameters of bone metabolism compared with prednisolone and might therefore have a significant clinical benefit over conventional GCs.[55] Similar effects have been described for the substance PF-04171327 (fosdagrocorat) in preclinical in vivo and in vitro assays, including a reduced influence on biomarkers of bone remodelling and glucose metabolism.[58] The first results of a subsequent randomized, double-blind phase 2 study comparing the safety and efficacy of multiple doses of PF-04171327 (1, 5, 10 or 15 mg) to that of prednisone (5 or 10 mg) and placebo in 323 patients with active RA have recently been published.[59,60] The data suggest that 10 mg of PF-04171327 are comparable in efficacy to 10 mg of prednisone, while even 15 mg of PF-04171327 is still non-inferior to 5 mg of prednisone with regard to their negative impact on the bone formation markers procollagen 1 N-terminal propeptide and osteocalcin.[59,60] So, although the underlying transactivation/transrepression theory might be less exact than originally believed, the drugs resulting from this hypothesis are still promising candidates for safer and more effective alternatives to conventional GCs.