CDK5 Inhibitors and Therapeutic Uses Thereof

Abstract

Natural occurring inhibitors of cyclin-dependent protein kinase 5 (Cdk5), isolated from the root of Rhodiola rosea are structurally different from the known Cdk inhibitors. They show selectivity among different Cdks and efficacy to inhibit Cdk via a mixed-type of inhibition, which should lead to less toxicity and side-effects. They are useful in preventing and treating diseases and disorders associated with aberrant Cdk5 activities, such as acute and/or chronic pain, neuropathic pain, diabetes mellitus, cancer, neurodegenerative diseases and neuropathological disorders.

1 . A compound comprising a backbone structure as follows: 
       
         
           
           
               
               
           
         
         wherein R 1-11  are independently same or different, being independently hydrogen or a substituent. 
       
     
     
         2 . A compound of  claim 1 , comprising a structure of the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A pharmaceutic composition, comprising a pharmaceutically effectively amount of a compound of  claim 1  and one or more pharmaceutically acceptable excipients. 
     
     
         4 . A pharmaceutic composition comprising a pharmaceutically effectively amount of compound of  claim 2  and one or more pharmaceutically acceptable excipients. 
     
     
         5 . A method of inhibiting Cdk5 enzyme in human cells, comprising contacting said Cdk5 enzyme with an amount of a compound of the following formula: 
       
         
           
           
               
               
           
         
         wherein R 1-7  are independently same or different, being independently hydrogen or a substituent. 
       
     
     
         6 . The method of  claim 5 , where said compound is selected from the group consisting of F119-C6, F199-C16, F199-C23, F199-C35, F199-C42 and F199-057. 
     
     
         7 . The method of  claim 5 , where R 1 , R 2  and R 3  of said compound are independently H, OH or OCH 3 . 
     
     
         8 . The method of  claim 5 , wherein R 4  of said compound is OH or OR 12 , where R 12  is a glucose group, 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 5 , wherein R 7  of said compound is OH or O-Glucose. 
     
     
         10 . The method of  claim 5 , wherein R 5  of said compound is H or ═O. 
     
     
         11 . The method of  claim 5 , further comprising administering said compound to a recipient who has been determined to be at risk of a disease or disorder associated with an aberrant Cdk5 activity. 
     
     
         12 . The method of  claim 11 , wherein said disease or disorder is neuropathic pain, stroke, brain trauma, epilepsy, or a neurodegenerative diseases. 
     
     
         13 . The method of  claim 12 , wherein said neurodegenerative diseases is amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease. 
     
     
         14 . A method of inhibiting Cdk5 enzyme in human cells, comprising contacting said Cdk5 enzyme with an amount of a compound as defined in  claim 1 . 
     
     
         15 . A method of inhibiting Cdk5 enzyme in human cells, comprising contacting said Cdk5 enzyme with an amount of a compound as defined in  claim 2 . 
     
     
         16 . A method of inhibiting Cdk5 enzyme in human cells, comprising contacting said Cdk5 enzyme with an amount of a substance selected from the group consisting of F199-C4, F199-C34 and F199-BU. 
     
     
         17 . The method of  claim 16 , further comprising administering said compound to a recipient who has been determined to be at risk of a disease or disorder associated with an aberrant Cdk5 activity. 
     
     
         18 . The method of  claim 17 , wherein said disease or disorder is neuropathic pain, stroke, brain trauma, epilepsy, or a neurodegenerative diseases. 
     
     
         19 . The method of  claim 18 , wherein said neurodegenerative diseases is amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease.