Tetrahydroisoquinolines as selective nadph oxidase 2 inhibitors

Abstract

Embodiments of bridged tetrahydroisoquinolines and methods for their use in selectively inhibiting nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 are disclosed. The disclosed compounds have a structure according to general formula I or a pharmaceutically acceptable salt thereof: wherein “ ” represents a single or double bond, R 1 is hydrogen, halogen, lower aliphatic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R a is hydrogen, —CH 2 R 2 , R 3 , or —SO 2 R 4 ; R 2 is lower aliphatic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 4 is lower aliphatic, or substituted or unsubstituted aryl; and R 5 is hydrogen, halogen, or lower aliphatic.

We claim: 
     
         1 . A method for treating or preventing a condition mediated by Nox2-related oxidative stress, comprising administering to a subject having, suspected of having, or at risk of developing, a condition mediated by Nox2 and/or reactive oxygen species produced by Nox2 activity, a therapeutically effective amount of a compound according to general formula I or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein “ ” represents a single or double bond;
 R 1  is hydrogen, halogen, lower aliphatic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R a  is hydrogen, —CH 2 R 2 , R 3 , or —SO 2 R 4 ; 
 R 2  is lower aliphatic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 3  is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 4  is lower aliphatic, or substituted or unsubstituted aryl; and 
 R 5  is hydrogen, halogen, or lower aliphatic, provided that: 
 when R 1  is bromo or hydrogen, then R a  is not hydrogen. 
 
       
     
     
         2 . The method of  claim 1 , wherein R 2  is C 4 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 
     
     
         3 . The method of  claim 2 , wherein:
 R 1  is hydrogen, halogen, or substituted or unsubstituted aryl;   R 4  is lower alkyl, or substituted or unsubstituted aryl; and   R 5  is hydrogen or halogen.   
     
     
         4 . The method of  claim 3 , wherein R 1  is halogen. 
     
     
         5 . The method of  claim 3 , wherein R 1  is bromo. 
     
     
         6 . The method of  claim 1 , wherein R a  is —CH 2 R 2  and R 2  is C 4 alkyl, substituted or unsubstituted C 6  aryl, or substituted or unsubstituted C 3 -C 5  heteroaryl. 
     
     
         7 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 1 , wherein the condition is a cardiovascular disease, a neurodegenerative disease, or cancer. 
     
     
         10 . The method of  claim 9 , wherein the cardiovascular disease is atherosclerosis, hypertension, ischemia reperfusion, cardiac hypertrophy, cardiomyopathy, stroke, restenosis, or any combination thereof. 
     
     
         11 . The method of  claim 9 , wherein the cardiovascular disease is atherosclerosis. 
     
     
         12 . The method of  claim 9 , wherein the neurodegenerative disease is Huntington's disease, Alzheimer's disease, Parkinson's disease, or any combination thereof. 
     
     
         13 . The method of  claim 1 , further comprising identifying the subject as having, suspected of having, or at risk of developing a condition mediated by Nox2 and/or reactive oxygen species produced by Nox2 activity by diagnosing the subject with a cardiovascular disease, a neurodegenerative disease, or cancer, or determining that the subject has one or more risk factors for a cardiovascular disease, a neurodegenerative disease, or cancer. 
     
     
         14 . The method of  claim 1 , further comprising administering to the subject:
 (i) a therapeutically effective amount of an additional active agent, wherein the additional active agent is an antimicrobial agent, an anti-inflammatory agent, an anesthetic, an antihypertensive, a statin, a fibrate, a bile acid sequestrant, a plant sterol, an omega-3 fatty acid, an anti-platelet drug, an anti-thrombolytic, an antiarrhythmic, digoxin, an anticoagulant, an antipsychotic, an antianxiety drug, an antidepressant, an acetylcholinesterase inhibitor, an N-methyl-D-aspartate receptor antagonist, a dopamine agonist, a monoamine oxidase B inhibitor, a catechol o-methyltransferase inhibitor, a muscle relaxant, nicotinic acid, carbidopa-levodopa, hydrogen sulfide, cyclosporine, tetrabenazine, amantadine, digoxin, or any combination thereof;   (ii) an adjunct therapy, wherein the adjunct therapy is stent placement, angioplasty, septal myectomy, ethanol ablation, an implantable cardioverter defibrillator, stem cell therapy, carotid endarterectomy, tissue plasminogen activator, brachytherapy, intracoronary radiation, deep brain stimulation, braces, physical therapy, occupational therapy, speech therapy, or any combination thereof; or   (iii) a combination thereof.   
     
     
         15 . The method of  claim 14 , wherein the compound and the additional active agent, the adjunct therapy, or combination thereof are administered to the subject simultaneously or sequentially in any order. 
     
     
         16 . The method of  claim 1 , wherein the compound has an IC 50  of ≦50 μM for inhibition of Nox2-mediated reactive oxygen species generation. 
     
     
         17 . The method of  claim 1 , wherein the compound selectively inhibits Nox2 activity compared to Nox1, Nox4, Nox5, and/or xanthine oxidase activity.