Compositions and methods for treating neurological disorders

Abstract

The present disclosure provides methods for treating neurological disorders, generally involving modulating protein kinase D1 (PKD1) activity levels in a neuron or glial cell in an individual in need thereof. The present disclosure provides antibodies specific for PKD1. The present disclosure provides a genetically modified non-human mammal deficient in PKD1 activity.

1 - 20 . (canceled) 
     
     
         21 . A method of treating a neurological disorder or a neurodegenerative disease in an individual, the method comprising administering to the individual a compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         J is independently N or CH; 
         each of R 8  and R 9  is independently —H or a Ring B substituent; 
         or R 8  and R 9 , taken together with the atoms to which they are attached, form an aromatic Ring C having exactly 5 ring atoms or exactly 6 ring atoms, wherein each ring atom is a carbon ring atom or a nitrogen ring atom, wherein Ring C has exactly 0, exactly 1, or exactly 2 ring nitrogen atoms, and wherein Ring C is fused to Ring B; 
         each of R 10 , R 11 , R 12 , and R 13  is independently —H or a Ring A substituent; or 
         each of R 12  and R 13  is independently a —H or Ring A substituent; and R 10  and R 11 , taken together with the atoms to which they are attached, form an aromatic Ring D having exactly 6 atoms, wherein each ring atom is a carbon ring atom, and wherein Ring D is fused to Ring A; or 
         each of R 10  and R 13  is independently —H or a Ring A substituent; and R 11  and R 12 , taken together with the atoms to which they are attached, form an aromatic Ring E having exactly 6 ring atoms, wherein each ring atom is a carbon ring atom, and wherein Ring E is fused to Ring A; or 
         each of R 10  and R 11  is independently —H or a Ring A substituent; and R 12  and R 13 , taken together with the atoms to which they are attached, form an aromatic Ring F having exactly 6 ring atoms, wherein each ring atom is a carbon ring atom, and wherein Ring F is fused to Ring A; and 
         each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  is independently —H; and 
         R 14  is —H. 
         in an amount effective to inhibit activity of protein kinase D1 (PKD1) in a neuronal cell and/or a glial cell in the individual. 
       
     
     
         22 . The method of  claim 21 , wherein one of R 10 , R 11 , R 12  or R 13  is a Ring A substituent. 
     
     
         23 . The method of  claim 22 , wherein one of R 10 , R 11 , R 12  or R 13  is halogen or a heteroaryl group. 
     
     
         24 . The method of  claim 23 , wherein one of R 10 , R 11 , R 12  or R 13  is halogen. 
     
     
         25 . The method of  claim 24 , wherein one of R 10 , R 11 , R 12  or R 13  is —Cl. 
     
     
         26 . The method of  claim 24 , wherein R 11  is —Cl. 
     
     
         27 . The method according  claim 23 , wherein one of R 10 , R 11 , R 12  or R 13  is a heteroaryl group. 
     
     
         28 . The method of  claim 27 , wherein the heteroaryl group is selected from pyridinyl, thienyl and pyrazolyl. 
     
     
         29 . The method of  claim 27 , wherein R 11  is selected from pyridinyl, thienyl and pyrazolyl. 
     
     
         30 . The method of  claim 29 , wherein R 11  is pyrazolyl. 
     
     
         31 . The method of  claim 21 , wherein J is N. 
     
     
         32 . The method of  claim 21 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         33 . The method of  claim 21 , wherein the neurodegenerative disease is Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, or Alzheimer's disease. 
     
     
         34 . The method of  claim 31 , wherein the neurodegenerative disease is Huntington's disease or Alzheimer's disease. 
     
     
         35 . The method of  claim 21 , wherein the neurological disorder is stroke, spinal cord injury, or head injury. 
     
     
         36 . A method of treating Huntington's disease in an individual, the method comprising administering to the individual diagnosed as having Huntington's disease, a compound of formula: 
       
         
           
           
               
               
           
         
         in an amount effective to inhibit activity of protein kinase D1 (PKD1) in a neuronal cell and/or a glial cell in the individual. 
       
     
     
         37 . A method of treating Alzheimer's disease in an individual, the method comprising administering to the individual diagnosed as having Alzheimer's disease, a compound of formula: 
       
         
           
           
               
               
           
         
         in an amount effective to inhibit activity of protein kinase D1 (PKD1) in a neuronal cell and/or a glial cell in the individual.