Tumor Necrosis Factor (TNF) is a potent pro-inflammatory cytokine whose dysregulation has been found to cause rheumatoid arthritis, stroke and a broad range of inflammatory disease. Inhibition of TNF receptors has become an effective means to ameliorate inflammatory disease, however, pan TNF-R antagonists increase risk of infection and malignancy. Using a novel structure based design approach to identify small molecule compounds that bind to an allosteric site on TNF-R1, thus inhibiting binding of TNF-alpha to TNF-R1 and reducing activation of the TNF-alpha/TNF-R1 signaling pathway, the inventors have uncovered a new class of compounds that are effective at inhibiting the pathologic side-effects of TNF signaling while preserving the patient's ability to mount an immune response against pathogens.  Lead candidates are potent, highly specific and have been demonstrated to ameliorate arthritis in vivo.