Small molecule treats multiple sclerosis in rodents

Scientists at the drugmaker Sanofi have identified a small molecule that can cross the blood-brain barrier and inhibit colony stimulating factor-1 receptor (CSF1R), a kinase that’s been linked to multiple sclerosis. The compound, known as RA03546849, is effective at treating multiple sclerosis in rodents.

Andrew Scholte, a principal scientist at Sanofi, walked attendees of the Division of Medicinal Chemistry’s “Kinases in Neuroscience” symposium through the campaign that produced the inhibitor during a talk on Tuesday at ACS Spring 2023, a meeting of the American Chemical Society.

The Sanofi researchers, who were led by Nellwyn Hagan and John L. Kane Jr. hypothesized that by inhibiting CSF1R, they could dampen the effects of microglia and infiltrating macrophages, which are cells in the central nervous system associated with inflammation and other hallmarks of multiple sclerosis. The challenge, Scholte said, was to find a small molecule that could cross into the brain and could inhibit CSF1R without also inhibiting other kinases, particularly tropomyosin-related kinases that are widely expressed in the central nervous system.

The medicinal chemistry team started with a compound reported in 2005 by chemists at GSK. Scholte told C&EN that the team made approximately 600 compounds in their search for a selective CSF1R inhibitor, eventually landing on RA03546849. Tests in a rodent model of multiple sclerosis showed the compound was effective at preventing damage to axons and neurological impairment.

Scholte declined to say if RA03546849 was moving on to clinical testing, but he said Sanofi is interested in treatments for multiple sclerosis and that this work shows inhibiting CSF1R is a sound strategy.