Protease inhibitors having enhanced features
View Patent ↗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.
1. A method comprising orally administering an HIV protease inhibitor conjugate to an individual infected with HIV as part of a treatment regimen that includes administration of a second active agent in addition to the HIV protease inhibitor conjugate, wherein the HIV protease inhibitor conjugate is mono-mPEG n -atazanavir having a structure:
where n is selected from 1, 3, 5, 6, and 7, and the HIV protease inhibitor has an increased therapeutic index and/or increased potency relative to atazanavir in unconjugated form, and further wherein said administering does not include co-administration of a CYP3A4 inhibitor.
2. The method of claim 1 , wherein the dose of the HIV protease inhibitor conjugate 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 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 of the HIV protease inhibitor conjugate administered is less than the dose of the corresponding HIV protease inhibitor in unconjugated form.
4. The method of claim 1 , wherein the administering does not include co-administration of ritonavir.
5. The method of claim 1 , wherein the protease inhibitor conjugate has a greater potency than atazanavir in unconjugated form.
6. 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, (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, and (iii) the HIV protease inhibitor conjugate is mono-mPEG n -atazanavir having a structure:
where n is selected from 1, 3, 5, 6, and 7.
7. In a method that comprises administering to an individual infected with HIV, atazanavir in combination with a CYP3A4 inhibitor, the improvement comprising administering atazanavir as a mono-mPEG n -atazanavir conjugate having a structure:
where n is selected from 1, 3, 5, 6, and 7, and further wherein said administering does not include co-administration of ritonavir.