Reversible inhibitors of S-adenosyl-L-homocysteine hydrolase and uses thereof

Abstract

The present invention provides compositions and methods for reversibly inhibiting S-adenosyl-L-homocysteine (SAH) hydrolase. The compounds of the present invention can be used in combination with an anti-hemorrhagic viral infection agent, an immunosuppressant, a homocysteine lowering agent, or an anti-neoplasm agent. The compositions and methods of the present invention can be used for the prevention and treatment of hemorrhagic virus infection, autoimmune diseases, autograft rejection, neoplasm, hyperhomocysteineuria, cardiovascular disease, stroke, Alzheimer's disease, or diabetes.

1 . A compound or a pharmaceutically acceptable salt thereof, having the formula (I): 
       
         
           
           
               
               
           
         
         wherein Z is selected from the group consisting of carbon and nitrogen, 
         R1 and R2 are the same or different, and are selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, alkenyl, alkoxy, amino, aryl, heteroaryl, and halogen; 
         R3 and R4 are the same or different and are selected from the group consisting of hydrogen, alkyl, acetyl, alkenyl, aryl, and heteroaryl; 
         X is selected from the group consisting of oxygen, nitrogen, and sulfur; and 
         Y is selected from the group consisting of hydrogen, a C 1-10  alkyl group, alkenyl, vinyl, aryl, and heteroaryl, provided that the compound is not (4-adenine-9-yl)-2-hydroxybutanoic acid. 
       
     
     
         2 . The compound of  claim 1 , wherein R1, R2, R3, and R4 are hydrogen. 
     
     
         3 . The compound of  claim 1 , wherein X is oxygen. 
     
     
         4 . The compound of  claim 1 , wherein Y is a C 1-10  alkyl group. 
     
     
         5 . The compound of  claim 1 , wherein R1, R2, R3, and R4 are hydrogen, X is oxygen, and Y is a C 1-10  alkyl group. 
     
     
         6 . The compound of  claim 1 , wherein the β carbon of said compound has a configuration selected from the group consisting of S, R, and a racemic mixture thereof. 
     
     
         7 . The compound of  claim 1 , wherein said compound has a K i  value less than 100 nM for a mammalian S- adenosyl-L-homocysteine (SAH) hydrolase in a biological medium. 
     
     
         8 . The compound of  claim 7 , wherein said mammal is human. 
     
     
         9 . The compound of  claim 1 , wherein said compound has a K i  value between about 1 nM and about 100 nm for a mammalian SAH hydrolase in a biological medium. 
     
     
         10 . The compound of  claim 9 , wherein said mammal is human. 
     
     
         11 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein said compound has a K i  value less than 100 nM for a mammalian SAH hydrolase in a biological medium. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein said mammal is human. 
     
     
         14 . The pharmaceutical composition of  claim 11 , wherein said compound has a K i  value between about 1 nM and about 100 nM for a mammalian SAH hydrolase in a biological medium. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein said mammal is human. 
     
     
         16 . The pharmaceutical composition of  claim 11 , wherein said composition is formulated for oral, parenteral, intranasal, topical, or injectable administration. 
     
     
         17 . The pharmaceutical composition of  claim 11 , wherein said composition is formulated in a solid or liquid dosage form. 
     
     
         18 . The pharmaceutical composition of  claim 11 , wherein said composition is formulated for oral administration in a dosage ranging from about 0.1 to about 20 mg/kg per day. 
     
     
         19 . The pharmaceutical composition of  claim 11 , wherein said composition is formulated for injectable administration in a dosage ranging from about 0.1 to about 20 mg/kg per day. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein said injectable administration is selected from the group consisting of intracavernous injection, subcutaneous injection, intravenous injection, intramuscular injection, and intradermal injection. 
     
     
         21 . A kit, comprising an effective amount of said composition of  claim 11 , and an instruction means for administering said composition. 
     
     
         22 . A method for reversibly inhibiting activity of a S-adenosyl-L-homocysteine (SAH) hydrolase in a mammal, comprising administering to a mammal to which such reversible inhibition is needed or desirable, an effective amount of a compound or a pharmaceutically acceptable salt thereof, having the formula (I): 
       
         
           
           
               
               
           
         
         wherein Z is selected from the group consisting of carbon and nitrogen, 
         R1 and R2 are the same or different, and are selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, alkenyl, alkoxy, amino, aryl, heteroaryl, and halogen; 
         R3 and R4 are the same or different and are selected from the group consisting of hydrogen, alkyl, acetyl, alkenyl, aryl, and heteroaryl; 
         X is selected from the group consisting of oxygen, nitrogen, and sulfur; and 
         Y is selected from the group consisting of hydrogen, a C 1-10  alkyl group, alkenyl, vinyl, aryl, and heteroaryl, thereby reversibly inhibiting the activity of SAH hydrolase in said mammal. 
       
     
     
         23 . The method of  claim 22 , wherein said mammal is human. 
     
     
         24 . The method of  claim 23 , wherein said mammal is suspected of having a disease selected from the group consisting of hemorrhagic viral infection, autoimmune disease, autograft rejection, neoplasm, hyperhomocysteineuria, cardiovascular disease, stroke, Alzheimer disease, and diabetes. 
     
     
         25 . The method of  claim 24 , wherein said hemorrhagic viral infection is caused by a virus selected from the group consisting of a Bunyaviridaea, a Filoviridae, a Flaviviridae, and an Arenaviridae virus. 
     
     
         26 . The method of  claim 25 , wherein said Filoviridae virus is Ebola virus. 
     
     
         27 . The method of  claim 22 , wherein said administering step comprises administering an effective amount of said compound in the treatment of an autoimmune disease in said mammal. 
     
     
         28 . The method of  claim 22 , wherein said administering step comprises administering an effective amount of said compound in the treatment of allograft rejection in said mammal. 
     
     
         29 . The method of  claim 22 , wherein said administering step comprises administering an effective amount of said compound for lowering homocysteine in said mammal. 
     
     
         30 . The method of  claim 22 , wherein said administering step comprises administering an effective amount of said compound in the treatment of a neoplasm in said mammal. 
     
     
         31 . The method of  claim 30 , wherein said neoplasm is selected from the group consisting of adrenal gland, anus, auditory nerve, bile ducts, bladder, bone, brain, breast, bruccal, central nervous system, cervix, colon, ear, endometrium, esophagus, eye, eyelids, fallopian tube, gastrointestinal tract, head and neck, heart, kidney, larynx, liver, lung, mandible, mandibular condyle, maxilla, mouth, nasopharynx, nose, oral cavity, ovary, pancreas, parotid gland, penis, pinna, pituitary, prostate gland, rectum, retina, salivary glands, skin, small intestine, spinal cord, stomach, testes, thyroid, tonsil, urethra, uterus, vagina, vestibulocochlear nerve, and vulva neoplasm. 
     
     
         32 . The method of  claim 31 , wherein said neoplasm is selected from the group consisting of breast, ovary, stomach, prostate, colon and lung cancer. 
     
     
         33 . The method of  claim 22 , wherein said compound or a pharmaceutically acceptable salt thereof is not (4-adenine-9-yl)-2-hydroxybutanoic acid. 
     
     
         34 . A combination, comprising:
 a) an effective amount of a compound or a pharmaceutically acceptable salt thereof, having the formula (I):   
       
         
           
           
               
               
           
         
       
       wherein Z is selected from the group consisting of carbon and nitrogen, 
       R1 and R2 are the same or different, and are selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, alkenyl, alkoxy, amino, aryl, heteroaryl, and halogen; 
       R3 and R4 are the same or different and are selected from the group consisting of hydrogen, alkyl, acetyl, alkenyl, aryl, and heteroaryl; 
       X is selected from the group consisting of oxygen, nitrogen, and sulfur; and 
       Y is selected from the group consisting of hydrogen, a C 1-10  alkyl group, alkenyl, vinyl, aryl, and heteroaryl; and
 b) an effective amount of a compound selected from the group consisting of an anti-hemorrhagic viral infection agent, an immunosuppressant, a homocysteine lowering agent, and an anti-neoplasm agent. 
 
     
     
         35 . The combination of  claim 34 , wherein said anti-hemorrhagic viral infection agent inhibits interleukin-1 (IL-1), tumor necrosis factor (TNF), or a combination thereof. 
     
     
         36 . The combination of  claim 34 , wherein said anti-hemorrhagic viral infection agent is selected from the group consisting of an anti-viral vaccine, an anti-viral antibody, a viral-activated immune cell, and a viral-activated immune serum. 
     
     
         37 . The combination of  claim 34 , wherein said immunosuppressant is selected from the group consisting of cyclosporine, tacrolimus, an adrenocortical steroid, azathioprine, mycophenolate, cyclophosphamide, methotrexate, chlorambucil, vincristine, vinblastine, dactinomycin, an antithymocyte globulin, muromonab-CD3 monoclonal antibody, Rh 0 (D) immune globulin, methoxsalen, and thalidomide. 
     
     
         38 . The combination of  claim 34 , wherein said homocysteine lowering agent is selected from the group consisting of vitamin B 6 , vitamin B 12  and folate. 
     
     
         39 . The combination of  claim 34 , wherein said anti-neoplasm agent is selected from the group consisting of an anti-angiogenic agent, an alkylating agent, an antimetabolite, a natural product, a platinum coordination complex, an anthracenedione, a substituted urea, a methylhydrazine derivative, an adrenocortical suppressant, a hormone, an antagonist, an oncogene inhibitor, a tumor suppressor gene or protein, an anti-oncogene antibody, and an anti-oncogene antisense oligonucleotide. 
     
     
         40 . The combination of  claim 34 , further comprising a pharmaceutically acceptable carrier or excipient. 
     
     
         41 . The combination of  claim 34 , wherein said compound or a pharmaceutically acceptable salt thereof is not (4-adenine-9-yl)-2-hydroxybutanoic acid. 
     
     
         42 . A method for reversibly inhibiting activity of a SAH hydrolase in a mammal, comprising administering to a mammal to which such reversible inhibition is needed or desirable, an effective amount of a combination, wherein the combination comprises:
 a) an effective amount of a compound or a pharmaceutically acceptable salt thereof, having the formula (I):   
       
         
           
           
               
               
           
         
       
       wherein Z is selected from the group consisting of carbon and nitrogen, 
       R1 and R2 are the same or different, and are selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, alkenyl, alkoxy, amino, aryl, heteroaryl, and halogen; 
       R3 and R4 are the same or different and are selected from the group consisting of hydrogen, alkyl, acetyl, alkenyl, aryl, and heteroaryl; 
       X is selected from the group consisting of oxygen, nitrogen, and sulfur; and 
       Y is selected from the group consisting of hydrogen, a C 1-10  alkyl group, alkenyl, vinyl, aryl, and heteroaryl; and
 b) an effective amount of a compound selected from the group consisting of an anti-hemorrhagic viral infection agent, an immunosuppressant, a homocysteine lowering agent, and an anti-neoplasm agent, 
 
       thereby reversibly inhibiting said activity of SAH hydrolase in said mammal. 
     
     
         43 . The method of  claim 42 , wherein said compound or a pharmaceutically acceptable salt thereof is not (4-adenine-9-yl)-2-hydroxybutanoic acid. 
     
     
         44 . A kit, comprising an effective amount of a combination of  claim 34  and an instruction means for administering said combination. 
     
     
         45 . A method for identifying a candidate inhibitor compound capable of inhibiting S-adenosyl-L-homocysteine hydrolase (SAH) activity, comprising the steps of:
 a) constructing a computer model of the SAH binding pocket;   b) screening a plurality of compounds having the structure   
       
         
           
           
               
               
           
         
       
       wherein Z is selected from the group consisting of carbon and nitrogen; and
 c) identifying a compound that computationally binds to said binding pocket. 
 
     
     
         46 . The method of  claim 45 , further comprising the step of assaying said compound to determine the ability of said compound to inhibit SAH activity. 
     
     
         47 . A method for reversibly inhibiting activity of a SAH hydrolase, comprising contacting a SAH hydrolase with an effective amount of said compound of  claim 1  to reversibly inhibit the activity of said SAH hydrolase. 
     
     
         48 . A method for reversibly inhibiting activity of a SAH hydrolase, comprising contacting a SAH hydrolase with an effective amount of said combination of  claim 34  to reversibly inhibit the activity of said SAH hydrolase. 
     
     
         49 . The method of  claim 22 , which is used to inhibit lymphocyte proliferation, to inhibit production and/or release of IL-12P40, IL-12P70 and TNF-α or to inhibit primary antibody production in the mammal. 
     
     
         50 . The method of  claim 23 , wherein said mammal is suspected of having a disease selected from the group consisting of inflammatory Bowel disease, multiple sclerosis and autoimmune neuritis.