Multiple sclerosis (MS) is a devastating demyelinating disease of the central nervous system (CNS) that affects approximately 2.5 million people worldwide. Although a number of MS treatments are available, there remains a substantial unmet need for improved therapeutics. Therapies that target white blood cells can reduce disease activity and improve clinical outcomes in MS. Earlier we identified a small molecule inhibitor of a white blood cell receptor important in guiding inflammatory cell migration into the CNS. This compound, 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA), significantly suppresses MS-like symptoms in preclinical mouse models. Despite having multiple favorable features, α-NETA possesses certain liabilities that limit its potential for clinical development. To study preliminary structure-activity-relationship (SAR), we generated several analogs of α-NETA by modifying its key structural features and measuring IC<sub>50</sub> values for inhibition of chemerin-stimulated CMKLR1 signaling in vitro. Improved α-NETA analogs have the potential to impact the clinical management of MS and potentially other autoimmune or inflammatory disorders.

Novel CMKLR1 inhibitors and structure activity relationship studies for application in demyelinating disease

256th National Meeting (2018)

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