On the Horizon: Designer Glucocorticoids Providing Benefits Without Side Effects

BIRMINGHAM, ENGLAND — Increased understanding of the molecular mechanisms of glucocorticoids may eventually lead to the development of new agents that provide the clinical benefits without the attendant side effects that currently hamper the use of these drugs in rheumatic diseases.

It is now known that the anti-inflammatory and immunosuppressive effects of glucocorticoids primarily function via a process of negative regulation of gene expression, or transrepression, Frank Buttgereit, M.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.

“Glucocorticoids are very lipophilic molecules and are able to penetrate the cell membrane and bind to the cytosolic glucocorticoid receptor complex, which becomes activated and moves into the nucleus where it binds to specific DNA sites,” he explained. The result is upregulation of anti-inflammatory proteins and downregulation of inflammatory molecules such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α, he said.

An example of glucocorticoid transrepression is the effect on bone metabolism. “We currently think that TNF-α and IL-1 are able to induce osteoclasts and T cells to produce RANK ligand, which binds to the RANK receptor on osteoclast precursor cells and to the RANK receptor of the osteoclast,” he said. This results in an induced maturation of precursor cells into mature, very aggressive osteoclasts responsible for bone erosion and progression of osteoporosis. Downregulation of the TNF-α and IL-1 through transrepression retards these effects, he said.

While the benefits of these drugs stem from the genomic effects of transrepression, many of the unwanted cardiovascular, endocrine, and metabolic effects are mediated by a separate genomic process known as transactivation, said Dr. Buttgereit of the department of rheumatology and clinical immunology, University Hospital of Humboldt University, Berlin. Certain enzymes involved in the development of diabetes, for example, are activated at the genomic level by glucocorticoids, and an ongoing research effort is intended to create designer glucocorticoids that preferentially induce transrepression and have little or no transactivating activity—obtaining the benefit without the adverse effects.

These agents, several of which have been developed, are known as selective glucocorticoid receptor agonists (SEGRAs). One of these compounds, AK 216348, has been shown in animal studies to have anti-inflammatory effects equivalent to those of prednisone but with fewer transactivating effects, Dr. Buttgereit said.

Drugs of a second type of compound that has been developed are known as nitric oxide glucocorticoids or nitrosteroids. These not only bind to the glucocorticoid receptor but also slowly release nitric oxide, resulting in synergistic anti-inflammatory effects. In vitro studies of a prototype nitrosteroid, NCX-1015, have suggested that, unlike prednisone, it does not activate unwanted osteoclast activity (Rheum. Dis. Clin. North. Am. 2005;31:1–17).

Further preclinical work and then clinical trials will be needed to determine if these preliminary findings hold up, Dr. Buttgereit said.

BIRMINGHAM, ENGLAND — Increased understanding of the molecular mechanisms of glucocorticoids may eventually lead to the development of new agents that provide the clinical benefits without the attendant side effects that currently hamper the use of these drugs in rheumatic diseases.

It is now known that the anti-inflammatory and immunosuppressive effects of glucocorticoids primarily function via a process of negative regulation of gene expression, or transrepression, Frank Buttgereit, M.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.

“Glucocorticoids are very lipophilic molecules and are able to penetrate the cell membrane and bind to the cytosolic glucocorticoid receptor complex, which becomes activated and moves into the nucleus where it binds to specific DNA sites,” he explained. The result is upregulation of anti-inflammatory proteins and downregulation of inflammatory molecules such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α, he said.

An example of glucocorticoid transrepression is the effect on bone metabolism. “We currently think that TNF-α and IL-1 are able to induce osteoclasts and T cells to produce RANK ligand, which binds to the RANK receptor on osteoclast precursor cells and to the RANK receptor of the osteoclast,” he said. This results in an induced maturation of precursor cells into mature, very aggressive osteoclasts responsible for bone erosion and progression of osteoporosis. Downregulation of the TNF-α and IL-1 through transrepression retards these effects, he said.

While the benefits of these drugs stem from the genomic effects of transrepression, many of the unwanted cardiovascular, endocrine, and metabolic effects are mediated by a separate genomic process known as transactivation, said Dr. Buttgereit of the department of rheumatology and clinical immunology, University Hospital of Humboldt University, Berlin. Certain enzymes involved in the development of diabetes, for example, are activated at the genomic level by glucocorticoids, and an ongoing research effort is intended to create designer glucocorticoids that preferentially induce transrepression and have little or no transactivating activity—obtaining the benefit without the adverse effects.

These agents, several of which have been developed, are known as selective glucocorticoid receptor agonists (SEGRAs). One of these compounds, AK 216348, has been shown in animal studies to have anti-inflammatory effects equivalent to those of prednisone but with fewer transactivating effects, Dr. Buttgereit said.

Drugs of a second type of compound that has been developed are known as nitric oxide glucocorticoids or nitrosteroids. These not only bind to the glucocorticoid receptor but also slowly release nitric oxide, resulting in synergistic anti-inflammatory effects. In vitro studies of a prototype nitrosteroid, NCX-1015, have suggested that, unlike prednisone, it does not activate unwanted osteoclast activity (Rheum. Dis. Clin. North. Am. 2005;31:1–17).

Further preclinical work and then clinical trials will be needed to determine if these preliminary findings hold up, Dr. Buttgereit said.

BIRMINGHAM, ENGLAND — Increased understanding of the molecular mechanisms of glucocorticoids may eventually lead to the development of new agents that provide the clinical benefits without the attendant side effects that currently hamper the use of these drugs in rheumatic diseases.

It is now known that the anti-inflammatory and immunosuppressive effects of glucocorticoids primarily function via a process of negative regulation of gene expression, or transrepression, Frank Buttgereit, M.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.

“Glucocorticoids are very lipophilic molecules and are able to penetrate the cell membrane and bind to the cytosolic glucocorticoid receptor complex, which becomes activated and moves into the nucleus where it binds to specific DNA sites,” he explained. The result is upregulation of anti-inflammatory proteins and downregulation of inflammatory molecules such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α, he said.

An example of glucocorticoid transrepression is the effect on bone metabolism. “We currently think that TNF-α and IL-1 are able to induce osteoclasts and T cells to produce RANK ligand, which binds to the RANK receptor on osteoclast precursor cells and to the RANK receptor of the osteoclast,” he said. This results in an induced maturation of precursor cells into mature, very aggressive osteoclasts responsible for bone erosion and progression of osteoporosis. Downregulation of the TNF-α and IL-1 through transrepression retards these effects, he said.

While the benefits of these drugs stem from the genomic effects of transrepression, many of the unwanted cardiovascular, endocrine, and metabolic effects are mediated by a separate genomic process known as transactivation, said Dr. Buttgereit of the department of rheumatology and clinical immunology, University Hospital of Humboldt University, Berlin. Certain enzymes involved in the development of diabetes, for example, are activated at the genomic level by glucocorticoids, and an ongoing research effort is intended to create designer glucocorticoids that preferentially induce transrepression and have little or no transactivating activity—obtaining the benefit without the adverse effects.

These agents, several of which have been developed, are known as selective glucocorticoid receptor agonists (SEGRAs). One of these compounds, AK 216348, has been shown in animal studies to have anti-inflammatory effects equivalent to those of prednisone but with fewer transactivating effects, Dr. Buttgereit said.

Drugs of a second type of compound that has been developed are known as nitric oxide glucocorticoids or nitrosteroids. These not only bind to the glucocorticoid receptor but also slowly release nitric oxide, resulting in synergistic anti-inflammatory effects. In vitro studies of a prototype nitrosteroid, NCX-1015, have suggested that, unlike prednisone, it does not activate unwanted osteoclast activity (Rheum. Dis. Clin. North. Am. 2005;31:1–17).

Further preclinical work and then clinical trials will be needed to determine if these preliminary findings hold up, Dr. Buttgereit said.