Prevention and treatment of benign prostatic hyperplasia using lonidamine and lonidamine analogs

Abstract

A method for treatment or prophylaxis of benign prostatic hyperplasia by administration of lonidamine or a lonidamine analog is provided. Also provided are unit dosage forms of lonidamine or an analog, useful for such treatment and prophylaxis.

1 . A method for treatment or prophylaxis of benign prostatic hypertrophy (BPH) comprising administering a lonidamine analog to a man in need of such treatment, wherein said lonidamine analog is a 1,3-substituted-indazole or pharmaceutically acceptable salt thereof.  
     
     
         2 . The method of  claim 1  wherein the lonidamine analog induces apoptosis in LNCaP cells (ATTC No. CRL-1740) and wherein an at least 3-fold greater level of apoptosis is induced in LNCaP cells than in PC3 cells (ATTC No. CRL-1435) when assayed at the concentration of analog at which the difference in the level of apoptosis in the two cell lines is greatest, with the proviso that the concentration of analog is not greater than 1 mM.  
     
     
         3 . The method of  claim 1  wherein the lonidamine analog inhibits hexokinase.  
     
     
         4 . The method of  claim 1  wherein the lonidamine analog has the structure:  
       
         
           
           
               
               
           
         
       
       where 
 R 2  is —Cl, —Br, —I, or —CH 3 , monosubstituted phenyl, substituted at the 2, 3, or 4 position; dichloro, dibromo, dimethyl, or chloro and methyl disubstituted phenyl, substituted at the 2 and 3 or 2 and 4 positions; or 2, 4, 5 trichlorophenyl; 
 Y is —(CH 2 )—;  
 n is one or zero;  
 when n is one, R 1  is —COOH, and X is —CH═CH—; and  
 when n is zero, R 1  is —COOH, —CONH 2 , —CONHNH 2 , —CONHN(CH 3 ) 2 , —CH 2 CH 2 OH, —CH 2 CH(OH)CH 2 OH, or CH 2 (CH 2 OH) 2 .  
 
 
     
     
         5 . The method of  claim 4  wherein R 2  is 4-chloro-2methylbenzyl, n is 0, and R 1  is —COOH.  
     
     
         6 . The method of  claim 4  wherein R 2  is 2,4-dichlorophenyl, n is 0, and R 1  is —CONHNH 2 .  
     
     
         7 . The method of  claim 4  wherein R 2  is 2,4-dichlorophenyl, n is one, X is —CH═CH—; and R 1  is —COOH.  
     
     
         8 . The method of  claim 1  wherein the subject is not being treated for cancer.  
     
     
         9 . The method of  claim 8  wherein the subject is not diagnosed with cancer.  
     
     
         10 . The method of  claim 1  wherein the subject has a serum PSA greater than about 2 ng/ml.  
     
     
         11 . The method of  claim 10  wherein the subject has a serum PSA less than about 10 ng/ml.  
     
     
         12 . The method of  claim 1  wherein the lonidamine analog is administered in combination with another treatment for BPH.  
     
     
         13 . The method of  claim 1 , wherein lonidamine is administered at least once per week for at least 4 weeks.  
     
     
         14 . The method of  claim 13  wherein the dose administered is between about 1 mg and about 300 mg.  
     
     
         15 . A method for treating BPH comprising (a) diagnosing BPH in a patient, (b) administering a lonidamine analog according to  claim 1  to the patient and (c) determining whether one or more manifestations of BPH are reduced in said patient.  
     
     
         16 . A method for treating BPH comprising (a) administering a lonidamine analog according to  claim 1  to a patient diagnosed with BPH and (b) determining whether one or more manifestations of BPH are reduced in said patient.