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 hyperproliferation of cells, comprising administering to a subject in need thereof an effective amount of a peripheral opioid antagonist and a chemotherapeutic agent, wherein the peripheral opioid antagonist is not a quaternary derivative of noroyxmorphone. 
     
     
         2 . The method of  claim 1 , wherein a disorder/disease is treated by the inhibitory effect of the peripheral opioid antagonist and the chemotherapeutic agent on the hyperproliferation of the cells. 
     
     
         3 . The method of  claim 2 , wherein the disorder/disease is a cancer. 
     
     
         4 . The method of  claim 1 , wherein the hyperproliferation is agonist-induced hyperproliferation. 
     
     
         5 . The method of  claim 5 , wherein the agonist-induced hyperproliferation is VEGF-induced hyperproliferation 
     
     
         6 . The method of  claim 1 , wherein the cells are endothelial cells. 
     
     
         7 . The method of  claim 6 , wherein the endothelial cells are vascular endothelial cells and the unwanted migration and/or proliferation of the vascular endothelial cells is abnormal/unwanted angiogenesis. 
     
     
         8 . The method of  claim 1 , wherein the subject is a human cancer patient, and the combination of the peripheral opioid antagonist and the chemotherapeutic agent is effective to inhibit or attenuate the hyperproliferaton of endothelial cells. 
     
     
         9 . The method of  claim 1 , wherein the peripheral opioid antagonist is administered simultaneously or sequentially with the chemotherapeutic agent. 
     
     
         10 . The method of  claim 1 , wherein the subject is taking concurrent opioid therapy. 
     
     
         11 . The method of  claim 1 , wherein the subject is not taking concurrent opioid therapy. 
     
     
         12 . The method of  claim 1 , wherein the chemotherapeutic agent is anti-metabolite, an anti-microtubule, an anti-neovascularization agent, or a tyrosine kinase inhibitor. 
     
     
         13 . The method of  claim 12 , wherein the anti-metabolite is 5-fluorouracil or gemcitabine. 
     
     
         14 . The method of  claim 12  wherein the tyrosine kinase inhibitor is an EGFR inhibitor. 
     
     
         15 . The method of  claim 14 , wherein the EGFR inhibitor is erlotinib. 
     
     
         16 . The method of  claim 12 , wherein the anti-neovascularization agent is a VEGF monoclonal antibody. 
     
     
         17 . The method of  claim 16 , wherein the anti-VEGF monoclonal anti-body is bevacizumab. 
     
     
         18 . The method of  claim 12 , wherein the anti-microtubule is vinorelbine, paclitaxel, docetaxel, or a combination thereof. 
     
     
         19 . The method of  claim 1 , wherein the peripheral opioid antagonist is a tertiary ammonium derivative of morphinan, benzomorphan or normorphinan. 
     
     
         20 . The method of  claim 1 , wherein the peripheral opioid antagonist is a N-substituted piperidine. 
     
     
         21 . The method of  claim 17 , wherein the N-piperidine is a piperidine-N-alkylcarbonylate. 
     
     
         22 . The method of  claim 18 , wherein the piperidine-N-alkylcarbonylate is a N-alkylamino-3,4,4 substituted piperidine. 
     
     
         23 . The method of  claim 19 , wherein N-alkylamino-3,4,4 substituted piperidine is alvimopan. 
     
     
         24 . The method of  claim 20 , wherein the piperidine-N-alkylcarboxylate is represented by formula (III): 
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen or alkyl; R 2  is hydrogen, alkyl, or alkenyl; R 3  is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R 4  is hydrogen, alkyl, or alkenyl; A is OR 5  or NR 6 R 7 ; wherein R 5  is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R 6  is hydrogen or alkyl; R 7  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, R 6  and R 7  form a heterocyclic ring selected from pyrrole and piperidine; B is 
       
       
         
           
           
               
               
           
         
         wherein R 8  is hydrogen or alkyl; R 9  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, R 8  and R 9  form a heterocyclic ring selected from pyrrole and piperidine; W is OR 10 , NR 11 R 12 , or OE; wherein R 10  is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkenyl, or aryl-substituted alkyl; R 11  is hydrogen or alkyl; R 12  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, R 11  and R 12  form a heterocyclic ring selected from pyrrole and piperidine; 
         E is 
       
       
         
           
           
               
               
           
         
         alkylene-substituted (C═O)D, or —R 13 OC(═O)R 14 ; wherein R 13  is alkyl-substituted alkylene; R 14  is alkyl; D is OR 15  or NR 16 R 17 ; wherein R 15  is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl substituted alkyl, or aryl-substituted alkyl; R 16  is hydrogen, alkyl, alkenyl, aryl, aryl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkyl substituted alkyl, or cycloalkenyl-substituted alkyl; R 17  is hydrogen or alkyl or, together with the nitrogen atom to which they are attached, R 16  and R 17  form a heterocyclic ring selected from the group consisting of pyrrole or piperidine; 
         Y is OR 18  or NR 19 R 20 ; wherein R 18  is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R 19  is hydrogen or alkyl; R 20  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, R 19  and R 20  form a heterocyclic ring selected from pyrrole and piperidine; R 21  is hydrogen or alkyl; and n is 0 to 4. 
       
     
     
         25 . The method of  claim 22 , wherein the N-alkylamino-3,4,4 substituted piperidine represented by formula (IV): 
       
         
           
           
               
               
           
         
       
     
     
         26 . A method of enhancing the efficacy of a cancer chemotherapeutic agent in a subject, the method comprising administering to a subject having a cancer the cancer chemotherapeutic agent and a peripheral mu-opioid antagonist, wherein the peripheral opioid antagonist is not a quaternary derivative of noroxymorphone, and wherein the chemotherapeutic agent is a tyrosine kinase inhibitor, an anti-microtubule, an anti-neovascularization agent or an antimetabolite. 
     
     
         27 . The method of  claim 26 , wherein the subject is taking concurrent opioid therapy. 
     
     
         28 . A method of achieving an effect in endothelial cells, comprising contacting the cells with an effective amount of a peripheral opioid antagonist and a chemotherapeutic agent, wherein the peripheral opioid antagonist is not a quaternary derivative of noroxymorphone and wherein the effect is inhibiting VEGF activity or Rho A activation. 
     
     
         29 . A method of treating cancer, comprising administering an effective amount of a peripheral opioid antagonist and a chemotherapeutic agent to a subject in need thereof to inhibit the hyperproliferation of cancer cells, wherein the peripheral opioid antagonist is not a quaternary derivative of noroxymorphone. 
     
     
         30 . The method of  claim 29 , wherein the cancer cells overexpress mu-opioid receptors.