Yesterday, in honor of Multiple Sclerosis Awareness Month, we wrote a blog article about Multiple Sclerosis (MS) and ion channels (see here: Multiple sclerosis and ion channels). Today, we’d like to spotlight a recent study on the discovery of new compounds with the potential to become novel remyelinating therapeutics for MS.

As we discussed in our previous post, MS is a debilitating disease that leads to significant physical and cognitive impairments due to damage to myelin in the CNS. While current therapies mainly focus on managing symptoms and reducing immune-mediated attacks, the discovery of compounds that can repair myelin damage by promoting the formation of new myelin-producing oligodendrocytes represents a fascinating shift towards regenerative medicine in MS treatment. However, there are currently no approved drugs that work by enhancing the myelin repair process.

Previous studies have identified a new way to potentially reverse myelin damage by targeting a specific enzyme in the cholesterol pathway called emopamil binding protein (EBP), which promotes the formation of myelinating oligodendrocytes from oligodendrocyte precursor cells (OPCs).

In a recent study, researchers from Genentech and Convelo Therapeutics presented a new brain-penetrant, orally bioavailable inhibitor of EBP, called compound 11, as a suitable in vivo tool molecule for further evaluation toward potential remyelination therapies.

A structure-based drug design approach from literature compound 1 (a published enhancer of OPC differentiation) led to the discovery of a hydantoin-based scaffold. This scaffold provided balanced physicochemical properties and potency and an improved in vitro safety profile. A subsequent medicinal chemistry campaign directed toward improving both safety and pharmacokinetic profiles led to the discovery of compound 11, a potent brain-penetrant EBP inhibitor.

The in vitro assessment of off-target activity using an expanded panel of 98 off-targets revealed a low risk of promiscuity for compound 11. The hERG safety assay, performed with the SyncroPatch 384 automated patch clamp platform, showed that compound 11 does not demonstrate strong activity against the hERG channel (IC50 = 8.2 μM).

Interestingly, unlike many pharmaceutical endeavors aimed at reducing metabolic turnover to prolong the drug’s action, the development of compound 11 took an unconventional route. The researchers focused on increasing metabolic turnover to avoid the risks associated with drug accumulation while maintaining its potency and brain-penetrant profile.

Compound 11 shined in its ability to engage its target within the brain, as evidenced by the accumulation of EBP substrate zymostenol following administration. This engagement translates into a significant increase in oligodendrocyte formation within human cortical organoids, laying a solid foundation for the therapeutic hypothesis that inhibiting EBP could be a viable strategy for remyelination in MS.

With its promising profile, compound 11 is gearing up for further studies, aiming to bring new hope to those living with MS.

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For more details, please refer to the paper here: https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c02396

Learn more about the SyncroPatch 384 here: https://www.nanion.de/products/syncropatch-384/