Excessive inflammation and TNFα synthesis cause morbidity and mortality in a spectrum of human diseases including sepsis, rheumatoid arthritis, and inflammatory bowel disease. TNFα specific antibodies that inhibit signaling, and represent the single most profitable segment of human therapeutics, are administered by intravenous injection. Identification of a small molecule surrogate for the biologic therapeutics has been prohibitively difficult due to the unusual structural features of the binding of TNF by its receptors. The mechanism has evolved to allow only trimers of TNFα to be agonists of the receptors, which form only in the case of sufficiently high local concentrations. Monomers of TNFα are inactive ligands. A further complication is the receptors are also trimeric aggregates. Consequently, inhibiting such a complex interaction with a small, orally bioavailable structure has not been accomplished. An alternative strategy is to inhibit signaling pathways that induce TNFα. A highly conserved, endogenous neurological pathway mediated by the vagus nerve detects and limits inflammation discovered by our collaborator, Dr. Kevin Tracey.