Is there a future for small molecule drugs in the treatment of rheumatic diseases?

Abstract

PURPOSE OF REVIEW: In this review, we outline the landscape of recent developments regarding small molecule compounds for the treatment of inflammatory disorders by discussing drug candidates currently in the pipeline. We also stress the fact that novel techniques are available to evaluate the safety of new therapeutics at an early stage of development. RECENT FINDINGS: Regulation of signal transduction has evolved into an important field of drug research, and small molecule inhibitors of a number of pathways are tested as new anti-inflammatory agents. For rheumatic diseases, specific Jak3 and Syk inhibitors are, so far, the most successful compounds due to their good efficacy, representing a significant advantage over p38 mitogen-activated protein kinase inhibitors. Additional benefit in the treatment of inflammatory diseases may be provided by targeting CD80, IL-12/IL-23, AP-1 transcription factor and receptors modulating cellular activation like chemokine receptors, Toll-like receptors and adenosine A3 receptor. SUMMARY: There is a big hope that novel small molecule drugs, which are rationally designed, based on scientific advancements and biotechnological improvements, will achieve or even exceed efficacy of protein drugs. Thereby, new therapeutic alternatives would be given, and chances for improved outcomes in the care of rheumatic patients provided.

Animal models of rheumatoid arthritis: How informative are they?

“…To address this, small molecular inhibitors (SMIs) have been investigated due to their lower manufacturing costs and oral availability (Stanczyk et al, 2008). SMIs are compounds with a molecular weight less than 1kDa and those targeting inflammation are largely kinase inhibitors.…”

Glucocorticoid resistance as a major drive in sepsis pathology

“…For this reason, several attempts have been made with inhibitors of inflammatory pathways to revert GCR, including inhibitors of TNF in an asthma model [127], inhibitors of IL1 in inner ear disease [128], p38 [111] and c-jun -JNK [159] in asthma and JAK3 in rheumatoid arthritis [160].…”

Novel pyrrolo[2,3-d]pyrimidines and pyrrolo[2,3-b]pyridines: design, synthesis, and in vivo TNF-α inhibitory activity

“…In the continuous efforts toward the discovery of therapeutics for the treatment of inflammatory conditions, orally active small molecules, that modify the pro-inflammatory cytokine release, have generated considerable interest in the pharmaceutical industry (Stanczyk, 2008). Tumor necrosis factor-a (TNF-a), one of the major pro-inflammatory cytokines, proved to be a potential target for these agents (Thomson and Lotze, 2003;Pfeffer, 2003;Wood, 2011).The over expression of TNF-a has been strongly implicated in a number of serious inflammatory disorders such as rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, and Crohn's disease (Thomson and Lotze, 2003;Pfeffer, 2003;Wood, 2011).…”