Heat shock proteins and cholesterol homeostasis

Abstract

Provided herewith are bioactive agents that increase the intracellular concentration and/or activity of one or more heat shock proteins, including Hsp70, for use in the treatment of a disease associated with dysregulation of cholesterol homeostasis.

1 . A method of treating a disease associate with a dysregulation of cholesterol homeostasis comprising administering to a subject in need thereof a bioactive agent, wherein the bioactive agent increases the intracellular concentration and/or activity of one or more heat shock proteins, including Hsp70. 
     
     
         2 . The method of  claim 1 , wherein the disease is associated with the cholesterol transporter ABCA1. 
     
     
         3 . The method of  claim 1 , wherein the disease is associated with modulated foam cells. 
     
     
         4 . The method of  claim 1 , wherein the disease is atherosclerosis, thrombus formation, thromboembolism, or resulting ischemia or infarction, associated with atherosclerosis. 
     
     
         5 . The method of  claim 1 , wherein the disease is Tangier disease. 
     
     
         6 . The method of  claim 1 , wherein the disease is familial HDL deficiency. 
     
     
         7 . The method of  claim 1 , wherein the disease is selected from: Antley-Bixler Syndrome, Hydrops-Ectopic Calcification-Moth-Eaten Skeletal Dysplasia (Greenberg dysplasia), Congenital Hemidysplasia with Ichthyosiform Nevus and Limb Defects Syndrome (CHILD), CK Syndrome, Conradi-Hünermann-Happle Syndrome (CPDX2, X-linked dominant chondrodysplasia punctate type 2), Lathosterolosis, Desmosterolosis, Mevalonate Kinase Deficiency (MKD) or (HIDS), and Mevalonate Aciduria. 
     
     
         8 . The method of  claim 1 , wherein the bioactive agent is a hydroxylamine derivative small molecule. 
     
     
         9 . The method of  claim 1 , wherein the bioactive agent is a hydroxylamine derivative small molecule that increases the intracellular concentration of Hsp70 by amplifying Hsp70 gene expression. 
     
     
         10 . The method of  claim 1 , wherein the bioactive agent is N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride (arimoclomol), a stereoisomer thereof, or an acid addition salt thereof. 
     
     
         11 . The method of  claim 1 , wherein the bioactive agent is selected from:
 the racemate of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride; an optically active stereoisomer of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride; an enantiomer of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride; (+)-R—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride; (−)-(S)—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride; an acid addition salt of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride; N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (BRX-345); N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate; (+)-R—N-[2-hydroxy-3-(1-piperidinyI)-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.   
     
     
         12 . The method of  claim 1 , wherein the bioactive agent is 5,6-dihydro-5-(1-piperidinyl)methyl-3-(3-pyridyl)-4H-1,2,4-oxadiazine (iroxanadine), a stereoisomer thereof, or an acid addition salt thereof. 
     
     
         13 . The method of  claim 1 , wherein the bioactive agent is selected from:
 the racemate of 5,6-dihydro-5-(1-piperidinyl)methyl-3-(3-pyridyl)-4H-1,2,4-oxadiazine; an optically active stereoisomer of 5,6-dihydro-5-(1-piperidinyl)methyl-3-(3-pyridyl)-4H-1,2,4-oxadiazine; an enantiomer of 5,6-dihydro-5-(1-piperidinyl)methyl-3-(3-pyridyl)-4H-1,2,4-oxadiazine; (+)-5,6-dihydro-5-(1-piperidinyl)methyl-3-(3-pyridyl)-4H-1,2,4-oxadiazine; (−)-5,6-dihydro-5-(1-piperidinyl)methyl-3-(3-pyridyl)-4H-1,2,4-oxadiazine; an acid addition salt of 5,6-dihydro-5-(1-piperidinyl)methyl-3-(3-pyridyl)-4H-1,2,4-oxadiazine; 5,6-dihydro-5-(1-piperidinyl)methyl-3-(3-pyridyl)-4H-1,2,4-oxadiazine citrate; 5,6-dihydro-5-(1-piperidinyl)methyl-3-(3-pyridyl)-4H-1,2,4-oxadiazine maleate; (+)-5,6-dihydro-5-(1-piperidinyl)methyl-3-(3-pyridyl)-4H-1,2,4-oxadiazine citrate; (−)-5,6-dihydro-5-(1-piperidinyl)methyl-3-(3-pyridyl)-4H-1,2,4-oxadiazine citrate; (+)-5,6-dihydro-5-(1-piperidinyl)methyl-3-(3-pyridyl)-4H-1,2,4-oxadiazine maleate; and (−)-5,6-dihydro-5-(1-piperidinyl)methyl-3-(3-pyridyl)-4H-1,2,4-oxadiazine maleate.   
     
     
         14 . The method of  claim 1 , wherein the bioactive agent is N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-pyridinecarboximidoyl chloride (bimoclomol), a stereoisomer thereof, or an acid addition salt thereof. 
     
     
         15 . The method of  claim 1 , wherein the bioactive agent is selected from:
 the racemate of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-pyridinecarboximidoyl chloride; an optically active stereoisomer of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-pyridinecarboximidoyl chloride; an enantiomer of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-pyridinecarboximidoyl chloride; (+)-R—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-pyridinecarboximidoyl chloride; (−)-(S)—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-pyridinecarboximidoyl chloride; an acid addition salt of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-pyridinecarboximidoyl chloride; N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-pyridinecarboximidoyl chloride citrate; N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-pyridinecarboximidoyl chloride maleate; (+)-R—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-pyridinecarboximidoyl chloride citrate; (−)-S—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-pyridinecarboximidoyl chloride citrate; (+)-R—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-pyridinecarboximidoyl chloride maleate; and (−)-S—N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-pyridinecarboximidoyl chloride maleate.   
     
     
         16 . The method of  claim 1 , wherein the bioactive agent is N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidamide dihydrochloride (BGP-15), a stereoisomer thereof, or an acid addition salt thereof. 
     
     
         17 . The method of  claim 1 , wherein the bioactive agent is selected from membrane-interactive compounds, anti-inflammatory drugs, prostaglandins, peroxidase proliferator-activated receptor-gamma agonists, tubulin-interacting anticancer agents, anti-neoplastic agents, Hsp90 inhibitors, proteasome inhibitors, serine protease inhibitors, histone deacetylase inhibitors, anti-ulcer drugs, heavy metals, alpha-adrenergic agonists, cyclopentenone prostanoids, L-type Ca++ channel blockers, and ryanodine receptor antagonists. 
     
     
         18 . The method of  claim 1 , wherein the bioactive agent is a membrane fluidizer selected from benzyl alcohol, heptanol, AL721, docosahexaenoic acid, oleyl alcohol, dimethylaminoethanol, A 2 C, and farnesol. 
     
     
         19 . The method of  claim 2 , wherein Hsp70 comprises a functional variant, wherein the functional variant of Hsp70 is a naturally occurring variant of Hsp70 or a fragment of a naturally occurring variant of Hsp70. 
     
     
         20 . A method of treating a disease associated with dysregulation of cholesterol homeostasis comprising administering to a subject in need thereof a pharmaceutical composition comprising a bioactive agent that increases the intracellular concentration and/or activity of one or more heat shock proteins, and optionally one or more pharmaceutically acceptable carrier.