Novel CMKLR1 Inhibitors for Application in Demyelinating Disease

Sci Rep. 2019 May 9;9(1):7178. doi: 10.1038/s41598-019-43428-8.


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-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA) that significantly suppressed disease onset in vivo. Here we directly compared α-NETA versus FDA-approved MS drug Tecfidera for clinical efficacy in EAE; characterized key safety/toxicity parameters for α-NETA; identified structure-activity relationships among α-NETA domains and CMKLR1 inhibition; and evaluated improved α-NETA analogs for in vivo efficacy. α-NETA proved safe and superior to Tecfidera in suppressing clinical EAE. In addition, we discovered structurally differentiated α-NETA analogs (primarily ortho- or para-methoxy substitutions) with significantly improved target potency in vitro and improved efficacy in vivo. These findings suggest that α-NETA-based CMKLR1 inhibitors may prove safe and effective in treating demyelinating diseases and potentially other autoimmune disorders.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Dimethyl Fumarate / therapeutic use
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Female
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Immunosuppressive Agents / chemistry
  • Immunosuppressive Agents / pharmacology
  • Immunosuppressive Agents / therapeutic use*
  • Mice
  • Mice, Inbred C57BL
  • Microsomes, Liver / metabolism
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology
  • Naphthalenes / therapeutic use*
  • Pregnane X Receptor / metabolism
  • Quaternary Ammonium Compounds / chemistry
  • Quaternary Ammonium Compounds / pharmacology
  • Quaternary Ammonium Compounds / therapeutic use*
  • Receptors, Chemokine / antagonists & inhibitors*
  • Receptors, Chemokine / metabolism
  • Structure-Activity Relationship


  • CMKLR1 protein, mouse
  • Immunosuppressive Agents
  • Naphthalenes
  • Pregnane X Receptor
  • Quaternary Ammonium Compounds
  • Receptors, Chemokine
  • 2-naphthoylethyltrimethylammonium
  • Dimethyl Fumarate