Arimoclomol for treating glucocerebrosidase associated disorders
The present invention relates to an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof (arimoclomol), for use in a method of treating glucocerebrosidase associated disorders.
1. A method of increasing glucocerebrosidase (GBA) level and/or activity in a cell by at least 10%, wherein the cell has one or more GBA gene mutation selected from L444P, D409H, D409V, E235A, E340A, E326K, N370S, N370S/1-BP ins 84G, V394L, A456P, V460V, C342G, G325R, P415R, Y133*, F213I, N188S, and IVS2+1G>A/N188S, comprising:
contacting the cell with an active pharmaceutical ingredient selected from: N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, a stereoisomer thereof, and an acid addition salt thereof.
2. The method of claim 1 , wherein the cell has reduced levels and/or activity of GBA compared to a control.
3. The method of claim 1 , wherein the GBA gene mutation is homozygous.
4. The method of claim 1 , wherein the GBA gene mutation is heterozygous.
5. The method of claim 1 , wherein the GBA gene mutation is compound heterozygous.
6. The method of claim 1 , wherein the active pharmaceutical ingredient:
i) is a racemate of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride; or
ii) is an optically active stereoisomer of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride; or
iii) is an enantiomer of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride; or
iv) is selected from the group consisting of (+)-R—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, and (−)-(S)—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride; or
v) is an acid addition salt of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride; or
vi) is selected from the group consisting of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, and N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate; or
vii) is selected from the group consisting of (+)-R—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate; (−)-S—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate; (+)-R—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate; and (−)-S—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate.
7. The method of claim 1 , wherein the cell is in vitro or in vivo.
8. The method of claim 1 , wherein the GBA level and/or activity is increased at least 1.5-fold.
9. The method of claim 1 , wherein the active pharmaceutical ingredient is (+)-R—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate.