Scientist have developed a small molecule drug candidate that selectively inhibits a rare class of calcium channel that’s implicated in the pathogenesis of Parkinson’s disease. They claim the compound could provide the basis for a completely new approach to treating Parkinson’s disease that blocks disease progression, rather than just alleviating its symptoms.
The L-type channel in dopaminergic neurons has a CaV1.3 pore-forming subunit, and previous attempts have failed to identify compounds that block this channel but not the more common L-type channel with a CaV1.2 pore-forming subunit. A team at Northwestern University, Evanston, now reports on the results of screening studies that identified compounds based on a pyrimidine-2,4,6-trione (PYT) scaffold that selectively block the CaV1.3 subunit calcium channels, and importantly display favorable pharmacological and absorption, distribution, metabolism, and excretion (ADME) properties, as well as low toxicity, brain penetration, and oral bioavailability.
Interestingly, the investigators’ initial screens of commercial libraries containing nearly 60,000 compounds failed to identify even one selective inhibitor of the CaV1.3 calcium channel. Rather, their initial hits resulted from screening a library of a few hundred compounds developed in the laboratory of team leader Richard B. Silverman, Ph.D. And while the compounds identified through this screen weren’t ideal in terms of potency and specificity, subsequent refinements to the basic PYT structure resulted in a compound, 1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-(1H,3H,5H)-trione, that was a far more potent and selective antagonist of the CaV1.3 channel.
Dr. Silverman, who originally discovered the compound that is now marketed as the neuropathic pain drug Lyrica (pregabalin), says the PYT molecule could offer a completely new mechanistic approach to stopping Parkinson’s disease in its tracks, rather than just treating the symptoms. “These are the first compounds to selectively target this channel,” states coresearcher D. James Surmeier, at Northwestern University Feinberg School of Medicine. “By shutting down the channel, we should be slow the progression of the disease or significantly reduce the risk that anyone would get Parkinson’s disease if they take this drug early enough.”
Drs. Silverman, Surmeier et al describe their work in Nature Communications, in a paper titled “CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson’s disease.”