Protease Inhibitors Having Enhanced Features

Abstract

Provided herein (among other things) are protease inhibitor compounds having enhanced features, along with methods for administering such compounds. For example, the subject compounds can be administered without concomitant administration of a CYP3A4 inhibitor, have increased therapeutic index and/or increased potency, and are low-resistance inducing in nature. Exemplary potent HIV protease inhibitors are mono-m-PEG3-atazanavir, mPEGn-N-darunavir (wherein n is 3 or 5), mPEGn-NHCO-saquinavir (wherein n is 5 or 7), and di-mPEG3-atazanavir.

1 . A method comprising administering an HIV protease inhibitor conjugate to an individual infected with HIV, wherein the HIV protease inhibitor conjugate has an increased therapeutic index and/or increased potency relative to the HIV protease inhibitor in unconjugated form. 
     
     
         2 . The method of  claim 1 , wherein the dose administered is (i) different than the dose of the corresponding HIV protease inhibitor in unconjugated form, when compared on a molar basis, and (ii) retains at least the same (or substantially the same) HIV protease inhibitor activity on a molar basis, when evaluated in a suitable model or individual. 
     
     
         3 . The method of  claim 2 , wherein the dose administered is less than the dose of the corresponding HIV protease inhibitor in unconjugated form. 
     
     
         4 . A method of increasing the potency of a small drug molecule by covalently attaching to the small molecule drug one or more water-soluble oligomers. 
     
     
         5 . The method of  claim 4 , wherein the small molecule drug is an HIV protease inhibitor. 
     
     
         6 . A method of administering a potent protease inhibitor therapy to an individual infected with a virus, wherein the potent protease inhibitor therapy does not include co-administration of a CYP3A4 inhibitor. 
     
     
         7 . The method of  claim 6 , wherein the potent protease inhibitor is administered in a CYP3A4-competent biological system. 
     
     
         8 . A method comprising administering an HIV protease inhibitor conjugate as a protease inhibitor monotherapy to a biological system infected with HIV, wherein: (i) in a biological model in which the HIV protease inhibitor conjugate is periodically added in a given molar amount over time, and in the same biological model in which the same HIV protease inhibitor in unconjugated form is periodically added over time in the same given molar amount, the biological model in which the corresponding HIV protease inhibitor in unconjugated form is added is more likely to exhibit HIV protease resistance, and (ii) the HIV protease inhibitor conjugate retains at least substantially the same HIV protease inhibitor activity on a molar basis in a suitable model or patient. 
     
     
         9 . The method of  claim 1 , wherein the protease inhibitor has the following structure: 
       
         
           
           
               
               
           
         
         wherein: 
       
       
         
           
           
               
               
           
         
       
       is a residue of a small molecule protease inhibitor;
 (a) is an integer having a value of 1-3, 
 X, in each occurrence, is a stable linkage; and 
 POLY, in each occurrence, is a water-soluble, non-peptidic oligomer. 
 
     
     
         10 . The method of  claim 9 , wherein the water-soluble, non-peptidic oligomer possesses from 1-30 monomers. 
     
     
         11 . The method of  claim 10 , wherein the water-soluble non-peptidic oligomer possesses a number of monomer subunits selected from 1, 2, 3, 4, 5, 6, 7, 9 and 10. 
     
     
         12 . The method of  claim 9 , where the water-soluble non-peptidic oligomer is an oligomeric (ethylene oxide). 
     
     
         13 . The method of  claim 12 , wherein the oligomeric (ethylene oxide) possesses an alkoxy or hydroxyl end-capping moiety. 
     
     
         14 . The method of  claim 9 , wherein the protease inhibitor is selected from atazanavir, darunavir, saquinavir, and tipranavir. 
     
     
         15 . The method of  claim 1 , wherein the protease inhibitor is selected from: 
       
         
           
           
               
               
           
         
         Mono-mPEGn-Atazanavir (n=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 
       
       
         
           
           
               
               
           
         
         Di-mPEGn-Atazanavir (n=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 
       
       
         
           
           
               
               
           
         
         mPEGn-N-Darunavir (n=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 
       
       
         
           
           
               
               
           
         
         mPEGn-O-Darunavir (wherein n=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 
       
       
         
           
           
               
               
           
         
         mPEGn-amide-Tipranavir (n=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 
       
       
         
           
           
               
               
           
         
         mPEGn-OCONH-Tipranavir (n=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 
       
       
         
           
           
               
               
           
         
         mPEGn-NHCO-Saquinavir (n=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10). 
       
     
     
         16 . A protease inhibitor conjugate having a structure as set forth in  claim 9 , wherein the potency of the protease inhibitor covalently attached to the water-soluble oligomer has a greater potency than the small drug molecule in unconjugated form. 
     
     
         17 . Use of an HIV protease inhibitor conjugate in a method of treating an individual infected with HIV, wherein the HIV protease inhibitor conjugate possesses an increased therapeutic index and/or increased potency relative to the HIV protease inhibitor in unconjugated form. 
     
     
         18 . Use of potent protease inhibitor therapy for treating an individual infected with a virus by administering a potent protease inhibitor to the individual absent co-administration of a CYP3A4 inhibitor. 
     
     
         19 . Use of an HIV protease inhibitor conjugate as a protease inhibitor monotherapy in a biological system infected with HIV, in a method which comprises administering the HIV protease inhibitor conjugate, wherein: (i) in a biological model in which the HIV protease inhibitor conjugate is periodically added in a given molar amount over time, and in the same biological model in which the same HIV protease inhibitor in unconjugated form is periodically added over time in the same given molar amount, the biological model in which the corresponding HIV protease inhibitor in unconjugated form is added is more likely to exhibit HIV protease resistance, and (ii) the HIV protease inhibitor conjugate retains at least substantially the same HIV protease inhibitor activity on a molar basis in a suitable model or patient.