DAPD combination therapy with inosine monophosphate dehydrogenase inhibitor
It has been unexpectedly found that a drug resistant strain of HIV exhibits the behavior of drug-naïve virus when given the combination of a β-D-1,3-dioxolanyl nucleoside and an IMPDH inhibitor. In one nonlimiting embodiment, the HIV strain is resistant to a β-D-1,3-dioxolanyl nucleoside.
1 . A pharmaceutical composition for the treatment or prophylaxis of an HIV infection in a host, comprising an effective amount of a β-D-1,3-dioxolanyl purine of the formula:
or its pharmaceutically acceptable salt, wherein
R is H, OH, Cl, NH 2 or NR 1 R 2 ; R 1 and R 2 are independently hydrogen, alkyl or cycloalkyl, and R 3 is H, alkyl, aryl, acyl, phosphate, including monophosphate, diphosphate or triphosphate or a stabilized phosphate moiety, including a phospholipid, or an etherlipidin combination with at least one inosine monophosphate dehydrogenase (IMPDH) inhibitor, optionally in a pharmaceutically acceptable carrier or diluent.
2 . The composition of claim 1 , wherein the β-D-1,3-dioxolanyl purine is (−)-(2R,4R)-2-amino-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]-adenine (DAPD).
3 . The composition of claim 1 , wherein the β-D-1,3-dioxolanyl purine is (−)-(2R,4R)-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]-guanine (DXG).
4 . The composition of any one of claims 1 - 3 , wherein the IMPDH inhibitor is selected from the group consisting of ribavirin, mycophenolic acid, benzamide riboside, tiazofurin, selenazofurin, 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide (EICAR) and (S)-N-3-[3-(3-methoxy-4-oxazol-5-yl-phenyl)-ureido]-benzyl-carbamic acid tetrahydrofuran-3 -yl-ester (VX-497).
5 . The composition of claim 4 , wherein the IMPDH inhibitors is mycophenolic acid.
6 . The composition of claim 4 , wherein the IMPDH inhibitors is ribavirin.
7 . The composition of claims 1 - 6 , wherein the β-D-1,3-dioxolanyl purine is enantiomerically enriched.
8 . The composition of claim 1 in a pharmaceutically acceptable carrier suitable for oral delivery.
9 . The composition of claim 1 in a pharmaceutically acceptable carrier suitable for intravenous delivery.
10 . The composition of claim 1 in a pharmaceutically acceptable carrier suitable for parenteral delivery.
11 . The composition of claim 1 in a pharmaceutically acceptable carrier-suitable for topical delivery.
12 . The composition of claim 1 in a pharmaceutically acceptable carrier suitable for systemic delivery.
13 . A method for the treatment or prophylaxis of a drug resistant strain of HIV infection in a host, comprising administering an effective amount of a β-D-1,3-dioxolanyl purine of the formula:
or its pharmaceutically acceptable salt, wherein
R is H, OH, Cl, NH 2 or NR 1 R 2 ; R 1 and R 2 are independently hydrogen, alkyl or cycloalkyl, and R 3 is H, alkyl, aryl, acyl, phosphate, including monophosphate, diphosphate or triphosphate or a stabilized phosphate moiety in combination or alternation with an inosine monophosphate dehydrogenase (IMPDH) inhibitors, optionally in a pharmaceutically acceptable carrier or diluent.
14 . The method of claim 13 , wherein the β-D-1,3-dioxolanyl purine is (−)-(2R,4R)-2-amino-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]-adenine (DAPD).
15 . The method of claim 13 , wherein the β-D-1,3-dioxolanyl purine is (−)-(2R,4R)-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]-guanine (DXG).
16 . The method of any one of claims 13 - 15 , wherein the IMPDH inhibitor is selected from the group consisting of ribavirin, mycophenolic acid, benzamide riboside, tiazofurin, selenazofurin, 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide (EICAR) and (S)-N-3-[3-(3-methoxy-4-oxazol-5-yl-phenyl)-ureido]-benzyl-carbamic acid tetrahydrofuran-3-yl-ester (VX-497).
17 . The method of claim 16 , wherein the IMPDH inhibitor is mycophenolic acid.
18 . The method of claim 16 , wherein the IMPDH inhibitor is ribavirin.
19 . The method of claim 16 , wherein the HIV infection is resistant to DAPD and/or DXG.
20 . The method of any one of claims 13 -19, wherein the host is a human.
21 . A method for the treatment or prophylaxis of HIV infection in a host, comprising administering an effective amount of a β-D-1,3-dioxolanyl purine of the formula:
or its pharmaceutically acceptable salt, wherein
R is H, OH, Cl, NH 2 or NR 1 R 2 ; R 1 and R 2 are independently hydrogen, alkyl or cycloalkyl, and R 3 is H, alkyl, aryl, acyl, phosphate, including monophosphate, diphosphate or triphosphate or a stabilized phosphate moiety in combination or alternation with an inosine monophosphate dehydrogenase (IMPDH) inhibitors, optionally in a pharmaceutically acceptable carrier or diluent.
22 . The method of claim 21 , wherein the β-D-1,3-dioxolanyl purine is (−)-(2R,4R)-2-amino-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]-adenine (DAPD).
23 . The method of claim 21 , wherein the β-D-1,3-dioxolanyl purine is (−)-(2R,4R)-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]-guanine (DXG).
24 . The method of any one of claims 21 - 23 , wherein the IMPDH inhibitor is selected from the group consisting of ribavirin, mycophenolic acid, benzamide riboside, tiazofurin, selenazofurin, 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide (EICAR) and (S)-N-3-[3-(3-methoxy-4-oxazol-5-yl-phenyl)-ureido]-benzyl-carbamic acid tetrahydrofuran-3-yl-ester (VX-497).
25 . The method of claim 24 , wherein the IMPDH inhibitor is mycophenolic acid.
26 . The method of claim 24 , wherein the IMPDH inhibitor is ribavirin.
27 . The method of any one of claims 21 - 26 , wherein the host is a human.