Methods of inhibiting vascular permeability and apoptosis

Abstract

Agonists of vascular endothelial sphingosine-1-phosphate receptors are described. Compounds such as FTY720 can be phosphorylated by sphingosine kinase-2 into the phosphorylated forms which serve as sphingosine-1-phosphate receptor agonists. The vascular endothelial sphingosine-1-phosphate receptor agonists are employed in methods of treating a mammal for vascular permeability disorders and unwanted vascular endothelial cell apoptosis, and for the growth of new blood vessels. The sphingosine-1-phosphate receptor agonists can be used for the manufacture of a medicament for treating vascular permeability disorders and unwanted vascular endothelial cell apoptosis, and for the growth of new blood vessels

What is claimed is: 
     
         1 . A method of treating a mammal in need of treatment for an apoptosis-related disorder,
 comprising administering to the mammal in need of treatment for an apoptosis-related disorder a therapeutically effective amount of a vascular endothelial sphingosine-1-phosphate receptor agonist or a pharmaceutically acceptable salt thereof,   wherein the vascular endothelial sphingosine-1-phosphate receptor agonist is a 1,2-aminoalcohol, a pharmaceutically acceptable salt thereof, or a phosphorylated form thereof, having the formula   
       
         
           
           
               
               
           
         
         wherein R 1  is a substituted or unsubstituted straight- or branched carbon chain having 12 to 22 carbon atoms, and each of R 2 , R 3 , R 4  and R 5  are independently hydrogen or lower alkyl. 
       
     
     
         2 . The method of  claim 1 , wherein the apoptosis-related disorder is idiopathic cardiomyopathy, cardiomyopathy induced by drugs, cardiomyopathy induced by chronic alcoholism, familial cardiomyopathy, viral myocarditis, viral cardiomyopathy, cardiac infarction, cardiac angina, peripheral thrombosis, congestive heart failure, arrhythmia, cerebral stroke, subarachnoidal hemorrhage, cerebral infarction, cerebral thrombosis, or a combination comprising one or more of the foregoing disorders. 
     
     
         3 . The method of  claim 1 , wherein the apoptosis-related disorder is a neurodegenerative disease. 
     
     
         4 . The method of  claim 3 , wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, or resinitis pigmentosa. 
     
     
         5 . The method of  claim 1 , wherein R 1  is interrupted by a substituted or unsubstituted phenylene. 
     
     
         6 . The method of  claim 1 , wherein the vascular endothelial sphingosine-1-phosphate receptor agonist is 2-amino-2-[2-(4-octaphenyl)ethyl]propane-1,3 diol, 2-amino-2-methyl-4-[4-heptoxy-phenyl]butane-1-ol, 2-amino-3-phosphate-2-[2-4-octaphenyl)ethyl]propane-1-ol, 2-amino-2-methyl-4-[4-heptoxy-phenyl]1-diphosphoric acid, or a combination comprising one or more of the foregoing agonists. 
     
     
         7 . The method of  claim 6 , wherein the vascular endothelial sphingosine-1-phosphate receptor agonist is 2-amino-2-[2-(4-octaphenyl)ethyl]propane-1,3 diol, or 2-amino-2-methyl-4-[4-heptoxy-phenyl]butane-1-ol. 
     
     
         8 . The use of  claim 1 , wherein the vascular endothelial sphingosine-1-phosphate receptor agonist is phosphorylated by sphingosine kinase-2. 
     
     
         9 . The use of  claim 1 , wherein the vascular endothelial sphingosine-1-phosphate receptor is S1P 1 , S1P 2 , S1P 3 , S1P 4 , S1P 5 , or a combination comprising one or more of the foregoing receptors. 
     
     
         10 . A method of treating a mammal in need of treatment for apoptosis related to a neurodegenerative disease, comprising administering to the mammal in need of treatment for apoptosis related to a neurodegenerative disease a therapeutically effective amount of a vascular endothelial sphingosine-1-phosphate receptor agonist, wherein the vascular endothelial sphingosine-1-phosphate receptor agonist is a 1,2-aminoalcohol, a pharmaceutically acceptable salt thereof, or a phosphorylated form thereof, having the formula 
       
         
           
           
               
               
           
         
         wherein R 1  is a substituted or unsubstituted straight- or branched carbon chain having 12 to 22 carbon atoms, and each of R 2 , R 3 , R 4  and R 5  are independently hydrogen or lower alkyl. 
       
     
     
         11 . The method of  claim 10 , wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, or resinitis pigmentosa. 
     
     
         12 . The method of  claim 10 , wherein R 1  is interrupted by a substituted or unsubstituted phenylene. 
     
     
         13 . The method of  claim 10 , wherein the vascular endothelial sphingosine-1-phosphate receptor agonist is 2-amino-2-[2-(4-octaphenyl)ethyl]propane-1,3 diol, 2-amino-2-methyl-4-[4-heptoxy-phenyl]butane-1-ol, 2-amino-3-phosphate-2-[2-4-octaphenyl)ethyl]propane-1-ol, 2-amino-2-methyl-4-[4-heptoxy-phenyl]1-diphosphoric acid, or a combination comprising one or more of the foregoing agonists. 
     
     
         14 . The method of  claim 13 , wherein the vascular endothelial sphingosine-1-phosphate receptor agonist is 2-amino-2-[2-(4-octaphenyl)ethyl]propane-1,3 diol, or 2-amino-2-methyl-4-[4-heptoxy-phenyl]butane-1-ol. 
     
     
         15 . The use of  claim 1 , wherein the vascular endothelial sphingosine-1-phosphate receptor agonist is phosphorylated by sphingosine kinase-2. 
     
     
         16 . The use of  claim 1 , wherein the vascular endothelial sphingosine-1-phosphate receptor is S1P 1 , S1P 2 , S1P 3 , S1P 4 , S1P 5 , or a combination comprising one or more of the foregoing receptors.