Method for treating retinal degeneration with purinergic receptor agonists

Abstract

The present invention provides a method of preventing or treating retinal degeneration arising from pathophysiological or physical conditions. The method comprises administering to a patient a pharmaceutical composition comprising a purinergic P2Y receptor ligand, in an amount effective to elevate its extracellular concentration to activate retinal glial and neuronal cell surface P2Y receptors and mount a neuroprotective response. Methods of administering including intravitreal bolus and sustained administrations, transscleral delivery, topical, and systemic administrations. The pharmaceutical composition useful in this invention comprises a P2Y purinergic receptor agonist, which include uridine 5′-di- and triphosphate (UDP, UTP) and their analogs, adenosine 5′-diphosphate (ADP) and its analogs, cytidine 5′-di- and triphosphate (CDP, CTP) and their analogs, and dinucleoside polyphosphate compounds.

1 . A method of treating a retinal degenerative disease comprising: 
 administering to a patient a pharmaceutical composition comprising a therapeutically effective amount of a P2Y receptor agonist compound, wherein said amount is effective to increase the extracellular concentration of said agonist in retina such that cell surface P2Y receptors of retinal glial cells and neuronal cells are activated to mount a neuroprotective response, wherein said P2Y receptor agonist compound is a nucleotide diphosphate or a nucleotide triphosphate.    
     
     
         2 . The method according to  claim 1 , wherein said nucleotide diphosphate is selected from the group consisting of compounds of Formula Ia, IIa, IIIa, and pharmaceutically acceptable salts thereof:  
       
         
           
           
               
               
           
         
       
       Wherein: 
 X 1 , and X 2  are each independently either O −  or S − ;  
 Y is H or OH;  
 R 1  is selected from the group consisting of O, imido, methylene, and dihalomethylene;  
 R 2  is selected from the group consisting of H, halogen, alkyl, substituted alkyl, alkoxyl, nitro and azido;  
 R 3  is selected from the group consisting of H, alkyl, arylalkyl, acyl, arylacyl, and arylalkyl; and  
 R 4  is selected from the group consisting of —OR′, —SR′, NR′, and NR′R″, wherein R′ and R″ are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, alkoxyl, and aryloxyl, and with the proviso that R′ is absent when R 4  is double bonded from an oxygen or sulfur atom to the carbon at the 4-position of the pyrimidine ring;  
                     
 wherein:  
 R 1 , X 1 , X 2 , and Y are defined as in Formula Ia;  
 Z is H, Cl, or SR, wherein R is C 1 -C 20  saturated or unsaturated alkyl;  
 R′ 3  and R′ 4  are H while R′ 2  is nothing and there is a double bond between N1 and C-6, or  
 R′ 3  and R′ 4  are H while R′ 2  is O and there is a double bond between N-1 and C-6, or  
 R′ 3 , R′ 4 , and R′ 2  taken together are —CH═CH—, forming a ring from N-6 to N-1 with a double bond between N-6 and C-6;  
                     
 wherein:  
 R 1 , X 1 , X 2 , and Y are defined as in Formula Ia;  
 R 5  and R 6  are H while R 7  is nothing and there is a double bond between N-3 and C-4, or  
 R 5 , R 6  and R 7  taken together are —CH═CH—, forming a ring from N-3 to N-4 with a double bond between N-4 and C-4, optionally the hydrogen of the 4- or 5-position of the etheno ring is substituted with alkyl, substituted alkyl, alkoxyl, nitro, halo or azido.  
 
     
     
         3 . The method according to  claim 2 , wherein said nucleotide diphosphate is 5′-uridine diphosphate, 5′-adenosine diphosphate, or 5′-cytidine diphosphate.  
     
     
         4 . The method according to  claim 1 , wherein said nucleotide triphosphate is selected from the group consisting of compounds of Formula Ib, IIIb, and pharmaceutically acceptable salts thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X 1 , X 2  and X 3  are each independently either O −  or S − ,  
 Y is H or OH;  
 R 1  is O, imido, methylene or dihalomethylene;  
 R 2  is H or Br;  
 R 3  is selected from the group consisting of nothing, H, alkyl, acyl and arylalkyl; and.  
 R 4  is selected from the group consisting of —OR′, —SR′, NR′, and NR′R″, wherein R′ and R″ are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, alkoxyl, and aryloxyl, and with the proviso that R′ is absent when R 4  is double bonded from an oxygen or sulfur atom to the carbon at the 4-position of the pyrimidine ring;  
                     
 wherein:  
 R 1 , X 1 , X 2 , X 3 , and Y are defined as in Formula Ib, and  
 R 5  and R 6  are H while R 7  is nothing and there is a double bond between N-3 and C-4, or  
 R 5 , R 6  and R 7  taken together are —CH═CH—, forming a ring from N-3 to N-4 with a double bond between N-4 and C-4, optionally the hydrogen of the 4- or 5-position of the etheno ring is substituted with alkyl, substituted alkyl, alkoxyl, nitro, halogen or azide.  
 
     
     
         5 . The method according to  claim 4 , wherein said nucleotide triphosphate is uridine 5′-triphosphate, cytidine 5′-triphosphate, or 4-nitrophenylethenocytidine 5′-triphosphate.  
     
     
         6 . The method according to  claim 1 , wherein said compound is administered to a patient by an intravitreal delivery.  
     
     
         7 . The method according to  claim 1 , wherein said compound is administered to a patient by a transscleral delivery.  
     
     
         8 . The method according to  claim 1 , wherein said compound is administered to a patient by topical administration.  
     
     
         9 . The method according to  claim 8 , wherein said topical administration is via a carrier vehicle selected from the group consisting of drops of liquid, liquid washes, gels, ointments, sprays and liposomes.  
     
     
         10 . The method according to  claim 8 , wherein said topical administration comprises infusion of said compound to an ocular surface via a device selected from the group consisting of a pump-catheter system, a continuous or selective release device and a contact lens.  
     
     
         11 . The method according to  claim 1 , wherein said administering is systemic administration of said compound.  
     
     
         12 . The method according to  claim 11 , wherein said systemic administration is administration of a liquid/liquid suspension of said compound via nose drops or nasal spray, or administration of a nebulized liquid to oral or nasopharyngeal airways of said subject, such that a therapeutically effective amount of said compound contacts retinal tissues of said subject via systemic absorption and circulation.  
     
     
         13 . The method according to  claim 11 , wherein said systemic administration of said compound is accomplished by administering an oral form of said compound, such that a therapeutically effective amount of said compound contacts retinal tissues of said subject via systemic absorption and circulation.  
     
     
         14 . The method according to  claim 13 , wherein said oral form is a chewable gum.  
     
     
         15 . The method according to  claim 11 , wherein said systemic administration is administration of an injectable form of said compound, such that a therapeutically effective amount of said compound contacts retina tissues of said subject via systemic absorption and circulation.  
     
     
         16 . The method according to  claim 11 , wherein said systemic administration is administration of a suppository form of said compound, such that a therapeutically effective amount of said compound contacts retinal tissues of said subject via systemic absorption and circulation.  
     
     
         17 . The method according to  claim 11 , wherein said systemic administration is administration of an intra-operative instillation of a gel, cream, powder, foam, crystals, liposomes, spray or liquid suspension form of said compound, such that a therapeutically effective amount of said compound contacts the retinal tissues of said subject via systemic absorption and circulation.  
     
     
         18 . The method according to  claim 11 , wherein said systemic administration is administration of said compound in a form of a transdermal patch or a transdermal pad, such that a therapeutically effective amount of said compound contacts the retinal tissues of said subject via systemic absorption and circulation.  
     
     
         19 . The method according to  claim 1 , wherein said retinal degenerative diseases are inherited retinal degenerative diseases, acquired retinal degenerative diseases, or inflammation-induced retinal degenerative diseases.  
     
     
         20 . The method according to  claim 19 , wherein said inherited retinal degenerative disease is macular degeneration, Stargardt's disease, Best's disease, glaucoma, retinitis pigmentosa, or optic nerve degeneration.  
     
     
         21 . The method according to  claim 19 , wherein said acquired retinal degenerative disease is caused by cystoid macular edema, retinal detachment, photic damage, ischemic retinopathies due to venous or arterial occlusion or other vascular disorders, retinopathies due to trauma, surgery, or penetrating lesions of the eye, or peripheral vitreoretinopathy.  
     
     
         22 . The method according to  claim 19 , wherein said inflammation-induced retinal degenerative disease is caused by viral-, bacterial- or toxin-induced retinal degeneration, or uveitis.  
     
     
         23 . The method according to  claim 19 , wherein said inflammation-induced retinal degenerative disease results in optic neuritis.