Dimethylarginine Dimethylaminohydrolase Inhibitors and Methods of Use Thereof

Abstract

The present disclosure provides DDAH modulators. Thus, the present disclosure provides a method of treating a patient suffering from a disorder characterized by excessive NO production and/or elevated DDAH activity, the method comprising administering to said patient an effective amount of a compound of one of formulae I-X. The present disclosure also provides a pharmaceutical composition comprising a compound of one of formulae I-X.

1 .- 61 . (canceled) 
     
     
         62 . A method of treating an individual suffering from a fibrotic disorder a the method comprising administering to the individual an effective amount of a pharmaceutical formulation comprising:
 a) a dimethylarginine dimethylaminohydrolase (DDAH) inhibitor of one of the following formulas:   i) Formula Ia:   
       
         
           
           
               
               
           
         
         wherein 
         O 1  is N or CH; 
         R 1  is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; 
         R 2 , R 3 , R 4 , and R 5  are independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and 
         m is an integer from zero to four; 
         ii) Formula Ib: 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; 
         R 2 , R 3 , R 4 , and R 5  are independently selected from is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and 
         m is an integer from zero to four; 
         iii) Formula Ic: 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; 
         R 2 , R 3 , R 4 , and R 5  are independently selected from is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and 
         m is an integer from zero to four. 
       
     
     
         63 . The method of  claim 62 , wherein the formulation is administered with a carrier in the form of normal saline solution. 
     
     
         64 . The method of  claim 62 , wherein the formulation is administered locally to the airways of the patient. 
     
     
         65 . The method of  claim 62 , wherein the formulation is administered by inhalation. 
     
     
         66 . The method of  claim 62 , wherein the antagonist DDAH inhibitor is administered by insufflating an aerosol comprising the DDAH inhibitor. 
     
     
         67 . The method of  claim 62 , wherein the DDAH inhibitor is in a dry powder formulation. 
     
     
         68 . The method of  claim 62 , wherein the DDAH inhibitor is administered using a nebulizer. 
     
     
         69 . The method of  claim 62 , wherein the DDAH inhibitor is in an aqueous or ethanolic solution. 
     
     
         70 . The method of  claim 62 , wherein the individual is a human or is a non-human mammal. 
     
     
         71 . The method of  claim 62 , wherein the disorder is radiation-induced fibrosis. 
     
     
         72 . The method of  claim 62 , wherein the disorder is a dermal fibrotic disorder. 
     
     
         73 . The method of  claim 72 , wherein the administration is by topical administration or transdermal administration. 
     
     
         74 . The method of  claim 72 , wherein the fibrotic disorder is scleroderma, keloids, or hypertrophic scar. 
     
     
         75 . The method of  claim 62 , wherein the fibrotic disorder is liver fibrosis. 
     
     
         76 . The method of  claim 62 , wherein the fibrotic disorder is renal fibrosis. 
     
     
         77 . The method of  claim 62 , wherein individual does not have gastritis or gastric ulcer. 
     
     
         78 . The method of  claim 62 , wherein the DDAH inhibitor is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         79 . The method of  claim 62 , wherein the DDAH inhibitor is administered in a dosage range of from about 1 μg to about 10 mg. 
     
     
         80 . The method of  claim 62 , wherein the DDAH inhibitor is administered by oral administration. 
     
     
         81 . The method of  claim 62 , wherein the DDAH inhibitor is administered by intravenous administration.