SEGRAs: a novel class of anti-inflammatory compounds.

Abstract

Dissociated GCs show a separation between anti-inflammatory effects and certain side effects. This renders them as attractive compounds with better effect/side-effect profile as promising drug candidates and tool compounds for analyzing the molecular mechanisms of single side effects. A number of the GC-mediated side effects (e.g., osteoporosis, skin atrophy) are regulated in a very complex manner and use more than one molecular mechanism of the GR. Thus, theoretical predictions about the behavior of selective GR agonists regarding these effects are very difficult to make. Investigations of SEGRA compounds in relevant animal models will be the only way to get this important information. By availability of these tool compounds we now are in the advantageous situation to test them in vivo and to learn more about the possibilities and even the limitations of the selective GR agonists. Considering that the compounds have a non-steroidal structure, i.e., totally unrelated to steroids or other hormones at all, displaying only partially the molecular effects of GCs and are dissociated in their clinical profile, they should not be considered as GCs. Therefore, we introduced the term selective glucocorticoid receptor agonists (SEGRAs). These SEGRAs seem to represent a useful novel therapeutic modality which may complement existing therapeutic principles for the topical and especially the systemic treatment of inflammatory diseases. In summary, we and others are convinced that dissociated GCs are therapeutic compounds that exert many of the anti-inflammatory and immunosuppressive effects of standard GCs, while their potential to induce side effects is reduced. Whereas the in vitro dissociated profile of other compound classes (Belvisi et al. 2001) was not translated into a separation between anti-inflammatory activity and the induction of side effects in in vivo models, we could demonstrate this for the SEGRA compounds. Regarding the diversity of molecular mechanisms involved in mediating the complex side effects of GCs, it might be that only some of these unwanted effects can be reduced. However, as GCs are one of the most important anti-inflammatory therapeutics in the treatment of severe and chronic inflammatory diseases, even a partial reduction of side effect induction would be a great advantage for many patients.