Existing Evidence for the Repurposing of PARP-1 Inhibitors in Rare Demyelinating Diseases

Over the past decade, Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors have arisen as a novel and promising targeted therapy for breast cancer gene (BRCA)-mutated ovarian and breast cancer patients. Therapies targeting the enzyme, PARP-1, have since established their place as maintenance drugs for cancer. Here, we present existing evidence that implicates PARP-1 as a player in the development and progression of both malignancy and demyelinating disease. These findings, together with the proven clinical efficacy and marketed success of PARP-1 inhibitors in cancer, present the repurposing of these drugs for demyelinating diseases as a desirable therapeutic concept. Indeed, PARP-1 inhibitors are noted to demonstrate neuroprotective effects in demyelinating disorders such as multiple sclerosis and Parkinson’s disease, further supporting the use of these drugs in demyelinating, neuroinflammatory, and neurodegenerative diseases. In this review, we discuss the potential for repurposing PARP-1 inhibitors, with a focus on rare demyelinating diseases. In particular, we address the possible use of PARP-1 inhibitors in examples of rare leukodystrophies, for which there are a paucity of treatment options and an urgent need for novel therapeutic approaches

Design and Synthesis of Selective and Potent Orally Active S1P5 Agonists

Putting the brakes on demyelination: Fingolimod (FTY720) was recently shown to significantly decrease relapse rates in patients with multiple sclerosis. This drug attenuates the trafficking of harmful T-cells entering the brain by regulating sphingosine-1-phosphate (S1P) receptors. We designed, synthesized, evaluated 2H-phthalazin-1-one derivatives (e.g., 1 L) as selective S1P5 receptor agonists; these compounds are highly potent and selective, with good PK properties, and significant activity in oligodendrocytes