Methods of screening for compounds that modulate tafia activity, compounds, and methods of using the compounds

Abstract

Provided are methods of screening compounds for any aspirin-related activity other than TAFI inhibition, and also for non-inhibition of TAFI. Compounds identified by the screening methods can be used to treat, prevent or manage in a patient pain, fever, colon cancer, pancreatic cancer or an inflammatory, platelet aggregation, fibrinolytic or hemorrhagic disease or disorder. Also provided is a method of evaluating test compounds for TAFI inhibitory activity wherein the TAFI inhibitory activity of these test compounds is compared to the TAFI inhibitory activity of aspirin or its derivatives or metabolites. Further provided is a method of treating, preventing or managing in a patient, a hemorrhagic or thrombotic disease or disorder with high dose aspirin or aspirin derivatives or metabolites. Also contemplated is a method of treating, preventing or managing in a patient, pain, fever, colon cancer, pancreatic cancer or an inflammatory, platelet aggregation, fibrinolytic or hemorrhagic disease or disorder comprising administering aspirin or a derivative thereof or any other therapeutic having at least one desired therapeutic or prophylactic activity of aspirin to a patient in need thereof and administering to the patient a factor that promotes TAFIa activity, e.g. stabilized TAFIa, to ameliorate one or more adverse side effects of the therapeutic. Compounds identified by the methods of the invention are also provided.

1 . A method of identifying a compound which possesses (i) at least one aspirin activity selected from the group consisting of analgesia, anti-inflammation, fever reduction, anti-platelet aggregation, colon cancer prophylaxis, and pancreatic cancer prophylaxis, and (ii) no TAFIa-inhibition, comprising the steps of:
 a) exposing TAFIa to the test compound;   b) determining whether the test compound inhibits TAFIa activity and/or inhibits TAFI activation; and   c) determining whether at least one aspirin activity is retained by the test compound,   
       thereby identifying a compound that possesses at least one aspirin activity but not TAFIa-inhibitory activity. 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the aspirin activity is analgesia. 
     
     
         5 . The method of  claim 1 , wherein the aspirin activity is fever reduction. 
     
     
         6 . The method of  claim 1 , wherein the aspirin activity is anti-inflammation. 
     
     
         7 . The method of  claim 1 , wherein the aspirin activity is anti-platelet aggregation. 
     
     
         8 . The method of  claim 1 , wherein the aspirin activity is colon cancer prophylaxis. 
     
     
         9 . The method of  claim 1 , wherein the aspirin activity is pancreatic cancer prophylaxis. 
     
     
         10 . A method of treating pain, fever, inflammation, platelet-aggregation, colon cancer, pancreatic cancer, fibrinolytic, or thrombotic disease or disorder in a patient in need thereof, comprising administering a compound identified by the method of  claim 1  to the patient. 
     
     
         11 . (canceled) 
     
     
         12 . A compound identified by a method of evaluating inhibition of TAFIa activity by a test compound, in comparison with aspirin, salicylic acid, salicyluric acid or gentisic acid, comprising the steps of:
 a) exposing TAFIa to the test compound;   b) measuring inhibition of TAFIa activity by the test compound; and   c) comparing the inhibition of TAFIa activity by the test compound to inhibition of TAFIa activity by aspirin, SA, SU or gentisic acid,   thereby determining whether the test compound inhibits TAFIa activity more or less than aspirin, salicylic acid, salicyluric acid or gentisic acid.   
     
     
         13 - 18 . (canceled) 
     
     
         19 . A method of inhibiting TAFIa carboxypeptidase activity in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a TAFIa inhibiting compound selected from the group consisting of acetylsalicylic acid, salicylic acid, salicyluric acid, gentisic acid, glycyl amides and α-hydroxybenzoate derivatives, in an amount effective to inhibit TAFIa activity. 
     
     
         20 . (canceled) 
     
     
         21 . A method of treating, managing, or preventing a thrombotic disorder in a patient in need thereof, comprising administering to the patient a therapeutically or prophylactically effective amount of an inhibitor of TAFIa, wherein said inhibitor is selected from the group consisting of salicylic acid, salicyluric acid, gentisic acid, glycyl amides, acetylsalicylic acid and α-hydroxybenzoate derivatives, in an amount effective to inhibit TAFIa activity. 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 21 , wherein the thrombotic disease or disorder is selected from the group consisting of angina pectoris, chronic stable angina pectoris, heart attack, stroke, thromboembolic disease, myocardial infarction (MI), acute myocardial infarction (AMI), recurrent myocardial infarction, ischemic attack, transient ischemic attack (TIA), deep vein thrombosis, acute ischemic stroke, massive pulmonary embolism, disseminated intravascular coagulation (DIC), anti-phospholipid syndrome, familial thrombophilia, sepsis, arthritis, fulminant hepatitis, thrombosis, hemophilia and Von Willebrand disease. 
     
     
         24 - 26 . (canceled) 
     
     
         27 . A method of reducing bleeding side-effects of aspirin in a patient, said method comprising administering stabilized TAFIa to a patient receiving aspirin therapy. 
     
     
         28 . The method of  claim 27 , wherein aspirin is administered prior to, subsequent to, or concurrently with said administration of stabilized TAFIa. 
     
     
         29 . The method of  claim 21 , further comprising surgery on the patient. 
     
     
         30 . The method of  claim 29 , wherein the surgery is selected from the group consisting of organ transplant surgery, cardiopulmonary bypass surgery, coronary angioplasty, open heart surgery, heart valve surgery and removal of atherosclerotic plaques. 
     
     
         31 . The method of  claim 21 , further comprising administering an anti-coagulant to the patient. 
     
     
         32 . The method of  claim 31 , wherein the anti-coagulant is selected from the group consisting of tissue plasminogen activator, heparin, low molecular weight heparin, aspirin, actothrombin, hirudin, plasminogen, streptokinase, staphylokinase, urokinase and hirulong. 
     
     
         33 - 37 . (canceled) 
     
     
         38 . A method of treating, managing, or preventing a thrombotic disorder in a patient in need thereof, comprising administering to the patient a therapeutically or prophylactically effective amount of a pharmaceutical composition comprising a compound having the chemical structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         in an amount effective to inhibit TAFIa activity. 
       
     
     
         39 . (canceled) 
     
     
         40 . The method of  claim 38 , wherein the thrombotic disease or disorder is selected from the group consisting of angina pectoris, chronic stable angina pectoris, heart attack, stroke, thromboembolic disease, myocardial infarction (MI), acute myocardial infarction (AMI), recurrent myocardial infarction, ischemic attack, transient ischemic attack (TIA), deep vein thrombosis, acute ischemic stroke, massive pulmonary embolism, disseminated intravascular coagulation (DIC), anti-phospholipid syndrome, familial thrombophilia, sepsis, arthritis, fulminant hepatitis, thrombosis, hemophilia and Von Willebrand disease. 
     
     
         41 - 47 . (canceled)