Development of small molecules as anti-inflammatory and anti-resorptive drugs

Abstract

Rheumatoid arthritis is an auto-immune inflammatory disease that leads to stiff and swollen joints. Patients also have severe bone destruction of the affected joints and another common symptom of rheumatoid arthritis is a generalised bone loss that can lead to osteoporosis. Currently, there are many treatments for rheumatoid arthritis, which provide a recession of the inflammatory symptoms. However, none of these treatments are able to provide a complete protection against the rheumatoid arthritis-induced bone loss. Furthermore, the most effective available treatments such as glucocorticoids or the new biological drugs are not optimal since they either cause severe side effects or are very expensive and difficult to produce. Hence, there is a real need for new cost-effective treatments that can act on both inflammation and bone loss symptoms of rheumatoid arthritis. ABD compounds are small molecules, relatively easy to synthesize at reasonable cost. In this thesis, I discuss the effects of these small molecules on both rheumatoid arthritis-induced inflammation and bone loss. Daily treatments with the ketones ABD328 and ABD345, or with the sulphonamide ABD455 prevent inflammation in an animal model of rheumatoid arthritis. Furthermore, micro-CT and histology analysis showed that these treatments also provide a reliable protection against bone destruction of affected joints and generalised bone loss. In vitro data showed that this protective effect on bone was osteoclast specific. Indeed, Ishow here that treatment of other bone cells (such as osteoblasts or macrophages) with ABD compounds does not affect their biology. The mechanism of action of these compounds has also been studied and I show here that ABD compounds inhibit both inflammation and osteoclastogenesis by inhibiting the signalling pathways that are activated in response to pro-inflammatory cytokines such as TNF . This work led to the design and synthesis of further improved compounds, such as ABD599, that are currently considered as very interesting candidates for clinical trials. In conclusion, the ABD compounds, as small cost-effective molecules, represent a novel class of rheumatoid arthritis treatments by acting on both inflammation and bone loss symptoms of the disease.