Novel CMKLR1 Inhibitors for Application in Demyelinating Disease.

ABSTRACT: 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.

SUBMITTER: Kumar V 

PROVIDER: S-EPMC6509344 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature