Small molecules that disrupt leukocyte trafficking have proven effective in treating patients with multiple sclerosis (MS). We previously reported that chemerin receptor chemokine-like receptor 1 (CMKLR1) is required for maximal clinical and histological experimental autoimmune encephalomyelitis (EAE); and identified CMKLR1 small molecule antagonist 2-(-naphthoyl) ethyltrimethylammonium iodide (-NETA) that significantly suppressed disease onset in vivo. Here we directly compared -NETA versus FDA-approved MS drug Tecfidera for clinical efficacy in EAE; characterized key safety/toxicity parameters for -NETA; identified structure-activity relationships among -NETA domains and CMKLR1 inhibition; and evaluated improved -NETA analogs for in vivo efficacy. -NETA proved safe and superior to Tecfidera in suppressing clinical EAE. In addition, we discovered structurally differentiated -NETA analogs (primarily ortho- or para-methoxy substitutions) with significantly improved target potency in vitro and improved efficacy in vivo. These findings suggest that -NETA-based CMKLR1 inhibitors may prove safe and effective in treating demyelinating diseases and potentially other autoimmune disorders.