No abstract

Progressive multiple sclerosis is associated with metabolic failure of the axon and excitotoxicity that leads to chronic neurodegeneration. Global sodium-channel blockade causes side effects that can limit its use for neuroprotection in multiple sclerosis. Through selective targeting of drugs to lesions we aimed to improve the potential therapeutic window for treatment. This was assessed in the relapsing-progressive experimental autoimmune encephalomyelitis ABH mouse model of multiple sclerosis using conventional sodium channel blockers and a novel central nervous system-excluded sodium channel blocker (CFM6104) that was synthesized with properties that selectively target the inflammatory penumbra in experimental autoimmune encephalomyelitis lesions. Carbamazepine and oxcarbazepine were not immunosuppressive in lymphocyte-driven autoimmunity, but slowed the accumulation of disability in experimental autoimmune encephalomyelitis when administered during periods of the inflammatory penumbra after active lesion formation, and was shown to limit the development of neurodegeneration during optic neuritis in myelin-specific T cell receptor transgenic mice. CFM6104 was shown to be a state-selective, sodium channel blocker and a fluorescent p-glycoprotein substrate that was traceable. This compound was >90% excluded from the central nervous system in normal mice, but entered the central nervous system during the inflammatory phase in experimental autoimmune encephalomyelitis mice. This occurs after the focal and selective downregulation of endothelial p-glycoprotein at the blood-brain barrier that occurs in both experimental autoimmune encephalomyelitis and multiple sclerosis lesions. CFM6104 significantly slowed down the accumulation of disability and nerve loss in experimental autoimmune encephalomyelitis. Therapeutic-targeting of drugs to lesions may reduce the potential side effect profile of neuroprotective agents that can influence neurotransmission. This class of agents inhibit microglial activity and neural sodium loading, which are both thought to contribute to progressive neurodegeneration in multiple sclerosis and possibly other neurodegenerative diseases.

We report the discovery of a new class of neuroprotective voltage-dependent sodium channel modulators exemplified by (5-(1-benzyl-1H-indazol-3-yl)-1,2,4-oxadiazol-3-yl)methanamine 11 (CFM1178). The compounds were inhibitors of [(14)C]guanidinium ion flux in rat forebrain synaptosomes and displaced binding of the sodium channel ligand [(3)H]BW202W92. 11 and the corresponding N(2)-benzyl isomer, 38 (CFM6058), demonstrated neuroprotective activity in hippocampal slices comparable to sipatrigine. CYP450 enzyme inhibition observed with 11 was reduced with 38. In electrophysiological experiments on dissociated hippocampal neurons, these two compounds caused use- and voltage-dependent block of sodium currents. Sodium channel isoform profiling against Na(v)1.1-1.8 demonstrated that the standard sodium channel blocker lamotrigine had modest activity against Na(v)1.1, while sipatrigine was generally more potent and less selective. 11 and 38 showed potent activity against Na(v)1.6, pointing to pharmacological block of this isoform being consistent with the neuroprotective effect. 38 also showed use dependent block of Na(v)1.6 in HEK cells.

A one-pot chemo-enzymatic synthesis of highly enantiomerically enriched O-acetylcyanohydrins has been developed. The bimetallic (salen)titanium complex 1 is used to convert aldehydes into nonracemic (R)-O-acetylcyanohydrins with 61 to 93 % enantiomeric excess. A lipase enzyme is then used to hydrolyse the unwanted (S) enantiomer of the product, leaving (R)-O-acetylcyanohydrins with 80 to Ͼ99 % enantiomeric excess and in 75 to 96 % overall yield. Of ten lipase enzymes investigated, Candida antarctica lipase-B (CAL-B) has been shown to be the most suitable and the conditions for its use have been optimised. Although no single solvent has been found in which both catalyst 1 and CAL-B gave