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-(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.

• Authors: Vineet Kumar, Melissa LaJevic, Mallesh Pandrala, Sam A Jacobo, Sanjay V Malhotra, Brian A Zabel
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 7178 (05 09 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31073181 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

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

Topics

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