Use of opioid antagonists to attenuate endothelial cell proliferation and migration

Abstract

The invention provides methods of attenuating, e.g., inhibiting or reducing, cellular proliferation and migration, particularly endothelial cell proliferation and migration, including that associated with angiogenesis, using opioid antagonists, including, but not limited to, those that are peripherally restricted antagonists.

1 . A method of inhibiting abnormal migration and/or proliferation of cells in a subject, the method comprising administering to the subject an amount of a peripheral opioid receptor antagonist as the sole active agent, effective to inhibit the abnormal migration and/or proliferation of cells, wherein the peripheral opioid antagonist is not a quaternary derivative of noroxymorphone. 
     
     
         2 . The method of  claim 1 , wherein the cells are endothelial cells. 
     
     
         3 . The method of  claim 1 , wherein a disease is treated by the inhibitory effect of the peripheral opioid antagonist on the abnormal migration and/or proliferation of endothelial cells 
     
     
         4 . The method of  claim 3 , wherein the disease is a cancer. 
     
     
         5 . The method of  claim 1 , wherein the subject is a human cancer patient, and the amount of the peripheral opioid receptor antagonist is effective to attenuate abnormal migration and/or proliferation of endothelial cells. 
     
     
         6 . The method of  claim 2 , wherein the abnormal migration or proliferation of endothelial cells is abnormal migration or proliferation of vascular endothelial cells. 
     
     
         7 . The method of  claim 6 , wherein the abnormal migration or proliferation of vascular endothelial cells is abnormal angiogenesis. 
     
     
         8 . The method of  claim 1 , wherein the subject is taking concurrent opioid therapy. 
     
     
         9 . The method of  claim 1 , wherein the subject is not taking concurrent opioid therapy. 
     
     
         10 . The method of  claim 1 , wherein the subject is taking concurrent chronic opioid therapy. 
     
     
         11 . The method of  claim 1 , wherein the subject is not taking concurrent chronic opioid therapy. 
     
     
         12 . The method of  claim 1 , wherein the peripheral opioid antagonist is a tertiary morphinan derivative, a piperidine-N-alkylcarboxylate, or a tertiary benzomorphan. 
     
     
         13 . The method of  claim 1 , wherein the peripheral opioid antagonist is a tertiary ammonium derivative of morphinan, benzomorphan or normorphinan. 
     
     
         14 . The method of  claim 1 , wherein the peripheral opioid antagonist is a N-substituted piperidine. 
     
     
         15 . The method of  claim 12 , wherein the piperidine-N-alkylcarbonylate is a N-alkylamino-3,4,4 substituted piperidine. 
     
     
         16 . The method of  claim 15 , wherein N-alkylamino-3,4,4 substituted piperidine is alvimopan. 
     
     
         17 . The method of  claim 12 , wherein the piperidine-N-alkylcarboxylate is represented by formula (III): 
       
         
           
           
               
               
           
         
       
       wherein R1 is hydrogen or alkyl; R2 is hydrogen, alkyl, or alkenyl; R3 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R4 is hydrogen, alkyl, or alkenyl; A is OR5 or NR6R7; wherein R5 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R6 is hydrogen or alkyl; R7 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl or aryl-substituted alkyl, or alkylene-substituted B or together with the nitrogen atom to which they are attached, R6 and R7 form a heterocyclic ring selected from pyrrole and piperidine; B is 
       
         
           
           
               
               
           
         
       
       wherein R8 is hydrogen or alkyl; R9 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl or aryl-substituted alkyl or together with the nitrogen atom to which they are attached, R8 and R9 form a heterocyclic ring selected from pyrrole and piperidine; W is OR10, NR11R12, or OE; wherein R10 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkenyl, or aryl-substituted alkyl; R11 is hydrogen or alkyl; R12 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aryl-substituted alkyl, or alkylene-substituted C(═O)Y or, together with the nitrogen atom to which they are attached, R11 and R12 form a heterocyclic ring selected from pyrrole and piperidine;
 E is 
 
       
         
           
           
               
               
           
         
       
       alkylene-substituted (C═O)D, or —R13OC(═O)R14; wherein R13 is alkyl-substituted alkylene; R14 is alkyl; D is OR15 or NR16R17; wherein R15 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl substituted alkyl, or aryl-substituted alkyl; R16 is hydrogen, alkyl, alkenyl, aryl, aryl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkyl substituted alkyl, or cycloalkenyl-substituted alkyl; R17 is hydrogen or alkyl or, together with the nitrogen atom to which they are attached, R16 and R17 form a heterocyclic ring selected from the group consisting of pyrrole or piperidine;
 Y is OR18 or NR19R20; wherein R18 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R19 is hydrogen or alkyl; R20 is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl or, together with the nitrogen atom to which they are attached, R19 and R20 form a heterocyclic ring selected from pyrrole and piperidine; R21 is hydrogen or alkyl; and n is 0 to 4. 
 
     
     
         18 . The method of  claim 15 , wherein the N-alkylamino-3,4,4 substituted piperidine represented by formula (IV): 
       
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 20 , wherein the peripheral opioid antagonist is alvimopan. 
     
     
         20 . A method of achieving an effect in endothelial cells, comprising contacting the cells with an effective amount of a peripheral opioid antagonist, wherein opioid antagonist is not a quaternary derivative of noroxymorphone and wherein the effect is inhibiting VEGF activity or inhibiting Rho A activation. 
     
     
         21 . A method of reducing the risk of recurrence of a cancer or tumor after medical intervention, comprising administering a peripheral opioid antagonist to a cancer patient at the time of the intervention, wherein the peripheral opioid antagonist is not a quaternary derivative of noroxymorphone.