1-(phenylmethyl)benzimidazole and Arthritis--Rheumatoid

Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures. The second phase of discovery focused on the

Topics: Administration, Oral; Allosteric Regulation; Animals; Arthritis, Rheumatoid; Autoimmune Diseases; Biological Products; Drug Design; Ligands; Mice; Tumor Necrosis Factor-alpha